Mercurial > repos > willmclaren > ensembl_vep

--- a/variant_effect_predictor/.#variant_effect_predictor.pl.1.10	Fri Aug 03 10:04:48 2012 -0400
+++ /dev/null	Thu Jan 01 00:00:00 1970 +0000
@@ -1,1426 +0,0 @@
-#!/usr/bin/perl
-
-=head1 LICENSE
-
-  Copyright (c) 1999-2011 The European Bioinformatics Institute and
-  Genome Research Limited.  All rights reserved.
-
-  This software is distributed under a modified Apache license.
-  For license details, please see
-
-    http://www.ensembl.org/info/about/code_licence.html
-
-=head1 CONTACT
-
-  Please email comments or questions to the public Ensembl
-  developers list at <dev@ensembl.org>.
-
-  Questions may also be sent to the Ensembl help desk at
-  <helpdesk@ensembl.org>.
-
-=cut
-
-=head1 NAME
-
-Variant Effect Predictor - a script to predict the consequences of genomic variants
-
-http://www.ensembl.org/info/docs/variation/vep/vep_script.html
-
-Version 2.2
-
-by Will McLaren (wm2@ebi.ac.uk)
-=cut
-
-use strict;
-use Getopt::Long;
-use FileHandle;
-use Bio::EnsEMBL::Variation::Utils::Sequence qw(unambiguity_code);
-use Bio::EnsEMBL::Variation::Utils::VEP qw(
-    parse_line
-    vf_to_consequences
-    validate_vf
-    convert_to_vcf
-    load_dumped_adaptor_cache
-    dump_adaptor_cache
-    get_all_consequences
-    get_slice
-    build_full_cache
-    read_cache_info
-    get_time
-    debug
-    @OUTPUT_COLS
-    @REG_FEAT_TYPES
-    %FILTER_SHORTCUTS
-);
-
-# global vars
-my $VERSION = '2.3';
-
-# set output autoflush for progress bars
-$| = 1;
-
-# configure from command line opts
-my $config = &configure(scalar @ARGV);
-
-# run the main sub routine
-&main($config);
-
-# this is the main sub-routine - it needs the configured $config hash
-sub main {
-    my $config = shift;
-
-    debug("Starting...") unless defined $config->{quiet};
-
-    my $tr_cache = {};
-    my $rf_cache = {};
-
-    # create a hash to hold slices so we don't get the same one twice
-    my %slice_cache = ();
-
-    my @vfs;
-    my ($vf_count, $total_vf_count);
-    my $in_file_handle = $config->{in_file_handle};
-
-    # initialize line number in config
-    $config->{line_number} = 0;
-
-    # read the file
-    while(<$in_file_handle>) {
-        chomp;
-
-        $config->{line_number}++;
-
-        # header line?
-        if(/^\#/) {
-            if(defined($config->{vcf})) {
-                push @{$config->{headers}}, $_;
-            }
-            next;
-        }
-
-        # configure output file
-        $config->{out_file_handle} ||= &get_out_file_handle($config);
-
-        # some lines (pileup) may actually parse out into more than one variant
-        foreach my $vf(@{&parse_line($config, $_)}) {
-
-            $vf->{_line} = $_ ;#if defined($config->{vcf}) || defined($config->{original});
-
-            # now get the slice
-            if(!defined($vf->{slice})) {
-                my $slice;
-
-                # don't get slices if we're using cache
-                # we can steal them from transcript objects later
-                if((!defined($config->{cache}) && !defined($config->{whole_genome})) || defined($config->{check_ref}) || defined($config->{convert})) {
-
-                    # check if we have fetched this slice already
-                    if(defined $slice_cache{$vf->{chr}}) {
-                        $slice = $slice_cache{$vf->{chr}};
-                    }
-
-                    # if not create a new one
-                    else {
-
-                        $slice = &get_slice($config, $vf->{chr});
-
-                        # if failed, warn and skip this line
-                        if(!defined($slice)) {
-                            warn("WARNING: Could not fetch slice named ".$vf->{chr}." on line ".$config->{line_number}."\n") unless defined $config->{quiet};
-                            next;
-                        }
-
-                        # store the hash
-                        $slice_cache{$vf->{chr}} = $slice;
-                    }
-                }
-
-                $vf->{slice} = $slice;
-            }
-
-            # validate the VF
-            next unless validate_vf($config, $vf);
-
-            # make a name if one doesn't exist
-            $vf->{variation_name} ||= $vf->{chr}.'_'.$vf->{start}.'_'.$vf->{allele_string};
-
-            # jump out to convert here
-            if(defined($config->{convert})) {
-                &convert_vf($config, $vf);
-                next;
-            }
-
-            if(defined $config->{whole_genome}) {
-                push @vfs, $vf;
-                $vf_count++;
-                $total_vf_count++;
-
-                if($vf_count == $config->{buffer_size}) {
-                    debug("Read $vf_count variants into buffer") unless defined($config->{quiet});
-
-                    print_line($config, $_) foreach @{get_all_consequences($config, \@vfs, $tr_cache, $rf_cache)};
-
-                    debug("Processed $total_vf_count total variants") unless defined($config->{quiet});
-
-                    @vfs = ();
-                    $vf_count = 0;
-                }
-            }
-            else {
-                print_line($config, $_) foreach @{vf_to_consequences($config, $vf)};
-                $vf_count++;
-                $total_vf_count++;
-                debug("Processed $vf_count variants") if $vf_count =~ /0$/ && defined($config->{verbose});
-            }
-        }
-    }
-
-    # if in whole-genome mode, finish off the rest of the buffer
-    if(defined $config->{whole_genome} && scalar @vfs) {
-        debug("Read $vf_count variants into buffer") unless defined($config->{quiet});
-
-        print_line($config, $_) foreach @{get_all_consequences($config, \@vfs, $tr_cache, $rf_cache)};
-
-        debug("Processed $total_vf_count total variants") unless defined($config->{quiet});
-
-        debug($config->{filter_count}, "/$total_vf_count variants remain after filtering") if defined($config->{filter}) && !defined($config->{quiet});
-    }
-
-    debug("Executed ", defined($Bio::EnsEMBL::DBSQL::StatementHandle::count_queries) ? $Bio::EnsEMBL::DBSQL::StatementHandle::count_queries : 'unknown number of', " SQL statements") if defined($config->{count_queries}) && !defined($config->{quiet});
-
-    debug("Finished!") unless defined $config->{quiet};
-}
-
-# sets up configuration hash that is used throughout the script
-sub configure {
-    my $args = shift;
-
-    my $config = {};
-
-    GetOptions(
-        $config,
-        'help',                    # displays help message
-
-        # input options,
-        'config=s',                # config file name
-        'input_file=s',            # input file name
-        'format=s',                # input file format
-
-        # DB options
-        'species=s',               # species e.g. human, homo_sapiens
-        'registry=s',              # registry file
-        'host=s',                  # database host
-        'port=s',                  # database port
-        'user=s',                  # database user name
-        'password=s',              # database password
-        'db_version=i',            # Ensembl database version to use e.g. 62
-        'genomes',                 # automatically sets DB params for e!Genomes
-        'refseq',                  # use otherfeatures RefSeq DB instead of Ensembl
-        #'no_disconnect',           # disables disconnect_when_inactive
-
-        # runtime options
-        'most_severe',             # only return most severe consequence
-        'summary',                 # only return one line per variation with all consquence types
-        'per_gene',                # only return most severe per gene
-        'buffer_size=i',           # number of variations to read in before analysis
-        'chunk_size=s',            # size in bases of "chunks" used in internal hash structure
-        'failed=i',                # include failed variations when finding existing
-        'no_whole_genome',         # disables now default whole-genome mode
-        'whole_genome',            # proxy for whole genome mode - now just warns user
-        'gp',                      # read coords from GP part of INFO column in VCF (probably only relevant to 1KG)
-        'chr=s',                   # analyse only these chromosomes, e.g. 1-5,10,MT
-        'check_ref',               # check supplied reference allele against DB
-        'check_existing',          # find existing co-located variations
-        'check_alleles',           # only attribute co-located if alleles are the same
-        'check_frequency',         # enable frequency checking
-        'freq_filter=s',           # exclude or include
-        'freq_freq=f',             # frequency to filter on
-        'freq_gt_lt=s',            # gt or lt (greater than or less than)
-        'freq_pop=s',              # population to filter on
-
-        # verbosity options
-        'verbose',                 # print out a bit more info while running
-        'quiet',                   # print nothing to STDOUT (unless using -o stdout)
-        'no_progress',             # don't display progress bars
-
-        # output options
-        'output_file|o=s',           # output file name
-        'force_overwrite',         # force overwrite of output file if already exists
-        'terms=s',                 # consequence terms to use e.g. NCBI, SO
-        'coding_only',             # only return results for consequences in coding regions
-        'canonical',               # indicates if transcript is canonical
-        'ccds',                    # output CCDS identifer
-        'xref_refseq',             # output refseq mrna xref
-        'protein',                 # add e! protein ID to extra column
-        'hgnc',                    # add HGNC gene ID to extra column
-        'hgvs',                    # add HGVS names to extra column
-        'sift=s',                  # SIFT predictions
-        'polyphen=s',              # PolyPhen predictions
-        'condel=s',                # Condel predictions
-        'gene',                    # force gene column to be populated (disabled by default, enabled when using cache)
-        'regulatory',              # enable regulatory stuff
-        'convert=s',               # convert input to another format (doesn't run VEP)
-        'filter=s',                # run in filtering mode
-        'no_intergenic',           # don't print out INTERGENIC consequences
-        'gvf',                     # produce gvf output
-        'vcf',                     # produce vcf output
-        'original',                # produce output in input format
-        'no_consequences',         # don't calculate consequences
-
-        # cache stuff
-        'cache',                   # use cache
-        'write_cache',             # enables writing to the cache
-        'build=s',                 # builds cache from DB from scratch; arg is either all (all top-level seqs) or a list of chrs
-        'prefetch',                # prefetch exons, translation, introns, codon table etc for each transcript
-        'strip',                   # strips adaptors etc from objects before caching them
-        'rebuild=s',               # rebuilds cache by reading in existing then redumping - probably don't need to use this any more
-        'dir=s',                   # dir where cache is found (defaults to $HOME/.vep/)
-        'cache_region_size=i',     # size of region in bases for each cache file
-        'no_slice_cache',          # tell API not to cache features on slice
-        'standalone',              # standalone mode uses minimal set of modules installed in same dir, no DB connection
-        'skip_db_check',           # don't compare DB parameters with cached
-        'compress=s',              # by default we use zcat to decompress; user may want to specify gzcat or "gzip -dc"
-        'custom=s' => ($config->{custom} ||= []), # specify custom tabixed bgzipped file with annotation
-        'tmpdir=s',                # tmp dir used for BigWig retrieval
-        'plugin=s' => ($config->{plugin} ||= []), # specify a method in a module in the plugins directory
-
-        # debug
-        'cluck',                   # these two need some mods to Bio::EnsEMBL::DBSQL::StatementHandle to work. Clucks callback trace and SQL
-        'count_queries',           # counts SQL queries executed
-        'admin',                   # allows me to build off public hosts
-        'debug',                   # print out debug info
-    );
-
-    # print usage message if requested or no args supplied
-    if(defined($config->{help}) || !$args) {
-        &usage;
-        exit(0);
-    }
-
-    # config file?
-    if(defined $config->{config}) {
-
-        open CONFIG, $config->{config} or die "ERROR: Could not open config file \"".$config->{config}."\"\n";
-
-        while(<CONFIG>) {
-            next if /^\#/;
-            my @split = split /\s+|\=/;
-            my $key = shift @split;
-            $key =~ s/^\-//g;
-
-            if(defined($config->{$key}) && ref($config->{$key}) eq 'ARRAY') {
-                push @{$config->{$key}}, @split;
-            }
-            else {
-                $config->{$key} = $split[0];
-            }
-        }
-
-        close CONFIG;
-    }
-
-    # can't be both quiet and verbose
-    die "ERROR: Can't be both quiet and verbose!\n" if defined($config->{quiet}) && defined($config->{verbose});
-
-    # check file format
-    if(defined $config->{format}) {
-        die "ERROR: Unrecognised input format specified \"".$config->{format}."\"\n" unless $config->{format} =~ /pileup|vcf|guess|hgvs|ensembl|id|vep/i;
-    }
-
-    # check convert format
-    if(defined $config->{convert}) {
-        die "ERROR: Unrecognised output format for conversion specified \"".$config->{convert}."\"\n" unless $config->{convert} =~ /vcf|ensembl|pileup/i;
-    }
-
-    # connection settings for Ensembl Genomes
-    if($config->{genomes}) {
-        $config->{host} ||= 'mysql.ebi.ac.uk';
-        $config->{port} ||= 4157;
-    }
-
-    # connection settings for main Ensembl
-    else {
-        $config->{species} ||= "homo_sapiens";
-        $config->{host}    ||= 'ensembldb.ensembl.org';
-        $config->{port}    ||= 5306;
-    }
-
-    # refseq or core?
-    if(defined($config->{refseq})) {
-        die "ERROR: SIFT, PolyPhen and Condel predictions not available fore RefSeq transcripts\n" if defined $config->{sift} || defined $config->{polyphen} || defined $config->{condel};
-
-        $config->{core_type} = 'otherfeatures';
-    }
-    else {
-        $config->{core_type} = 'core';
-    }
-
-    # output term
-    if(defined $config->{terms}) {
-        die "ERROR: Unrecognised consequence term type specified \"".$config->{terms}."\" - must be one of ensembl, so, ncbi\n" unless $config->{terms} =~ /ensembl|display|so|ncbi/i;
-        if($config->{terms} =~ /ensembl|display/i) {
-            $config->{terms} = 'display';
-        }
-        else {
-            $config->{terms} = uc($config->{terms});
-        }
-    }
-
-    # check nsSNP tools
-    foreach my $tool(grep {defined $config->{lc($_)}} qw(SIFT PolyPhen Condel)) {
-        die "ERROR: Unrecognised option for $tool \"", $config->{lc($tool)}, "\" - must be one of p (prediction), s (score) or b (both)\n" unless $config->{lc($tool)} =~ /^(s|p|b)/;
-
-        die "ERROR: $tool not available for this species\n" unless $config->{species} =~ /human|homo/i;
-
-        die "ERROR: $tool not available in standalone mode\n" if defined($config->{standalone});
-
-        # use V2 of the Condel algorithm, possibly gives fewer false positives
-        if($tool eq 'Condel' && $config->{lc($tool)} =~ /1$/) {
-            $Bio::EnsEMBL::Variation::Utils::Condel::USE_V2 = 0;
-        }
-    }
-
-    # force quiet if outputting to STDOUT
-    if(defined($config->{output_file}) && $config->{output_file} =~ /stdout/i) {
-        delete $config->{verbose} if defined($config->{verbose});
-        $config->{quiet} = 1;
-    }
-
-    # summarise options if verbose
-    if(defined $config->{verbose}) {
-        my $header =<<INTRO;
-#----------------------------------#
-# ENSEMBL VARIANT EFFECT PREDICTOR #
-#----------------------------------#
-
-version $VERSION
-
-By Will McLaren (wm2\@ebi.ac.uk)
-
-Configuration options:
-
-INTRO
-        print $header;
-
-        my $max_length = (sort {$a <=> $b} map {length($_)} keys %$config)[-1];
-
-        foreach my $key(sort keys %$config) {
-            next if ref($config->{$key}) eq 'ARRAY' && scalar @{$config->{$key}} == 0;
-            print $key.(' ' x (($max_length - length($key)) + 4)).(ref($config->{$key}) eq 'ARRAY' ? join "\t", @{$config->{$key}} : $config->{$key})."\n";
-        }
-
-        print "\n".("-" x 20)."\n\n";
-    }
-
-    # check custom annotations
-    for my $i(0..$#{$config->{custom}}) {
-        my $custom = $config->{custom}->[$i];
-
-        my ($filepath, $shortname, $format, $type) = split /\,/, $custom;
-        $type ||= 'exact';
-        $format ||= 'bed';
-
-        # check type
-        die "ERROR: Type $type for custom annotation file $filepath is not allowed (must be one of \"exact\", \"overlap\")\n" unless $type =~ /exact|overlap/;
-
-        # check format
-        die "ERROR: Format $format for custom annotation file $filepath is not allowed (must be one of \"bed\", \"vcf\", \"gtf\", \"gff\", \"bigwig\")\n" unless $format =~ /bed|vcf|gff|gtf|bigwig/;
-
-        # bigwig format
-        if($format eq 'bigwig') {
-            # check for bigWigToWig
-            die "ERROR: bigWigToWig does not seem to be in your path - this is required to use bigwig format custom annotations\n" unless `which bigWigToWig 2>&1` =~ /bigWigToWig$/;
-        }
-
-        else {
-            # check for tabix
-            die "ERROR: tabix does not seem to be in your path - this is required to use custom annotations\n" unless `which tabix 2>&1` =~ /tabix$/;
-
-            # remote files?
-            if($filepath =~ /tp\:\/\//) {
-                my $remote_test = `tabix $filepath 1:1-1 2>&1`;
-                if($remote_test =~ /fail/) {
-                    die "$remote_test\nERROR: Could not find file or index file for remote annotation file $filepath\n";
-                }
-                elsif($remote_test =~ /get_local_version/) {
-                    debug("Downloaded tabix index file for remote annotation file $filepath") unless defined($config->{quiet});
-                }
-            }
-
-            # check files exist
-            else {
-                die "ERROR: Custom annotation file $filepath not found\n" unless -e $filepath;
-                die "ERROR: Tabix index file $filepath\.tbi not found - perhaps you need to create it first?\n" unless -e $filepath.'.tbi';
-            }
-        }
-
-        $config->{custom}->[$i] = {
-            'file'   => $filepath,
-            'name'   => $shortname || 'CUSTOM'.($i + 1),
-            'type'   => $type,
-            'format' => $format,
-        };
-    }
-
-    # check if using filter and original
-    die "ERROR: You must also provide output filters using --filter to use --original\n" if defined($config->{original}) && !defined($config->{filter});
-
-    # filter by consequence?
-    if(defined($config->{filter})) {
-
-        my %filters = map {$_ => 1} split /\,/, $config->{filter};
-
-        # add in shortcuts
-        foreach my $filter(keys %filters) {
-            my $value = 1;
-            if($filter =~ /^no_/) {
-                delete $filters{$filter};
-                $filter =~ s/^no_//g;
-                $value = 0;
-                $filters{$filter} = $value;
-            }
-
-            if(defined($FILTER_SHORTCUTS{$filter})) {
-                delete $filters{$filter};
-                $filters{$_} = $value for keys %{$FILTER_SHORTCUTS{$filter}};
-            }
-        }
-
-        $config->{filter} = \%filters;
-
-        $config->{filter_count} = 0;
-    }
-
-    # set defaults
-    $config->{user}              ||= 'anonymous';
-    $config->{buffer_size}       ||= 5000;
-    $config->{chunk_size}        ||= '50kb';
-    $config->{output_file}       ||= "variant_effect_output.txt";
-    $config->{tmpdir}            ||= '/tmp';
-    $config->{format}            ||= 'guess';
-    $config->{terms}             ||= 'display';
-    $config->{gene}              ||= 1 unless defined($config->{whole_genome}) && !defined($config->{cache});
-    $config->{cache_region_size} ||= 1000000;
-    $config->{dir}               ||= join '/', ($ENV{'HOME'}, '.vep');
-    $config->{compress}          ||= 'zcat';
-    $config->{tmpdir}            ||= '/tmp';
-
-    # frequency filtering
-    if(defined($config->{check_frequency})) {
-        foreach my $flag(qw(freq_freq freq_filter freq_pop freq_gt_lt)) {
-            die "ERROR: To use --check_frequency you must also specify flag --$flag\n" unless defined $config->{$flag};
-        }
-
-        # need to set check_existing
-        $config->{check_existing} = 1;
-    }
-
-    $config->{check_existing} = 1 if defined $config->{check_alleles};
-
-    # warn users still using whole_genome flag
-    if(defined($config->{whole_genome})) {
-        debug("INFO: Whole-genome mode is now the default run-mode for the script. To disable it, use --no_whole_genome") unless defined($config->{quiet});
-    }
-
-    $config->{whole_genome}      = 1 unless defined $config->{no_whole_genome};
-    $config->{include_failed}    = 1 unless defined $config->{include_failed};
-    $config->{chunk_size}        =~ s/mb?/000000/i;
-    $config->{chunk_size}        =~ s/kb?/000/i;
-    $config->{cache_region_size} =~ s/mb?/000000/i;
-    $config->{cache_region_size} =~ s/kb?/000/i;
-
-    # cluck and display executed SQL?
-    $Bio::EnsEMBL::DBSQL::StatementHandle::cluck = 1 if defined($config->{cluck});
-
-    # standalone needs cache, can't use HGVS
-    if(defined($config->{standalone})) {
-        $config->{cache} = 1;
-
-        die("ERROR: Cannot generate HGVS coordinates in standalone mode\n") if defined($config->{hgvs});
-        die("ERROR: Cannot use HGVS as input in standalone mode\n") if $config->{format} eq 'hgvs';
-        die("ERROR: Cannot use variant identifiers as input in standalone mode\n") if $config->{format} eq 'id';
-        die("ERROR: Cannot do frequency filtering in standalone mode\n") if defined($config->{check_frequency});
-    }
-
-    # write_cache needs cache
-    $config->{cache} = 1 if defined $config->{write_cache};
-
-    # no_slice_cache, prefetch and whole_genome have to be on to use cache
-    if(defined($config->{cache})) {
-        $config->{prefetch} = 1;
-        $config->{no_slice_cache} = 1;
-        $config->{whole_genome} = 1;
-        $config->{strip} = 1;
-    }
-
-    $config->{build} = $config->{rebuild} if defined($config->{rebuild});
-
-    # force options for full build
-    if(defined($config->{build})) {
-        $config->{prefetch} = 1;
-        $config->{gene} = 1;
-        $config->{hgnc} = 1;
-        $config->{no_slice_cache} = 1;
-        $config->{cache} = 1;
-        $config->{strip} = 1;
-        $config->{write_cache} = 1;
-    }
-
-    # connect to databases
-    $config->{reg} = &connect_to_dbs($config);
-
-    # complete dir with species name and db_version
-    $config->{dir} .= '/'.(
-        join '/', (
-            defined($config->{standalone}) ? $config->{species} : ($config->{reg}->get_alias($config->{species}) || $config->{species}),
-            $config->{db_version} || $config->{reg}->software_version
-        )
-    );
-
-    if(defined($config->{cache})) {
-        # read cache info
-        if(read_cache_info($config)) {
-            debug("Read existing cache info") unless defined $config->{quiet};
-        }
-    }
-
-    # include regulatory modules if requested
-    if(defined($config->{regulatory})) {
-        # do the use statements here so that users don't have to have the
-        # funcgen API installed to use the rest of the script
-        eval q{
-            use Bio::EnsEMBL::Funcgen::DBSQL::RegulatoryFeatureAdaptor;
-            use Bio::EnsEMBL::Funcgen::DBSQL::MotifFeatureAdaptor;
-            use Bio::EnsEMBL::Funcgen::MotifFeature;
-            use Bio::EnsEMBL::Funcgen::RegulatoryFeature;
-            use Bio::EnsEMBL::Funcgen::BindingMatrix;
-        };
-
-        if($@) {
-            die("ERROR: Ensembl Funcgen API must be installed to use --regulatory\n");
-        }
-    }
-
-    # warn user cache directory doesn't exist
-    if(!-e $config->{dir}) {
-
-        # if using write_cache
-        if(defined($config->{write_cache})) {
-            debug("INFO: Cache directory ", $config->{dir}, " not found - it will be created") unless defined($config->{quiet});
-        }
-
-        # want to read cache, not found
-        elsif(defined($config->{cache})) {
-            die("ERROR: Cache directory ", $config->{dir}, " not found");
-        }
-    }
-
-    # suppress warnings that the FeatureAdpators spit if using no_slice_cache
-    Bio::EnsEMBL::Utils::Exception::verbose(1999) if defined($config->{no_slice_cache});
-
-    # get adaptors
-    if(defined($config->{cache}) && !defined($config->{write_cache})) {
-
-        # try and load adaptors from cache
-        if(!&load_dumped_adaptor_cache($config)) {
-            &get_adaptors($config);
-            &dump_adaptor_cache($config) if defined($config->{write_cache});
-        }
-
-        # check cached adaptors match DB params
-        else {
-            my $dbc = $config->{sa}->{dbc};
-
-            my $ok = 1;
-
-            if($dbc->{_host} ne $config->{host}) {
-
-                # ens-livemirror, useastdb and ensembldb should all have identical DBs
-                unless(
-                    (
-                        $dbc->{_host} eq 'ens-livemirror'
-                        || $dbc->{_host} eq 'ensembldb.ensembl.org'
-                        || $dbc->{_host} eq 'useastdb.ensembl.org'
-                    ) && (
-                        $config->{host} eq 'ens-livemirror'
-                        || $config->{host} eq 'ensembldb.ensembl.org'
-                        || $config->{host} eq 'useastdb.ensembl.org'
-                    )
-                ) {
-                    $ok = 0;
-                }
-
-                # but we still need to reconnect
-                debug("INFO: Defined host ", $config->{host}, " is different from cached ", $dbc->{_host}, " - reconnecting to host") unless defined($config->{quiet});
-
-                &get_adaptors($config);
-            }
-
-            if(!$ok) {
-                if(defined($config->{skip_db_check})) {
-                    debug("INFO: Defined host ", $config->{host}, " is different from cached ", $dbc->{_host}) unless defined($config->{quiet});
-                }
-                else {
-                    die "ERROR: Defined host ", $config->{host}, " is different from cached ", $dbc->{_host}, ". If you are sure this is OK, rerun with -skip_db_check flag set";
-                }
-            }
-        }
-    }
-    else {
-        &get_adaptors($config);
-        &dump_adaptor_cache($config) if defined($config->{write_cache})
-    }
-
-    # reg adaptors (only fetches if not retrieved from cache already)
-    &get_reg_adaptors($config) if defined($config->{regulatory});
-
-    # get terminal width for progress bars
-    unless(defined($config->{quiet})) {
-        my $width;
-
-        # module may not be installed
-        eval q{
-            use Term::ReadKey;
-        };
-
-        if(!$@) {
-            my ($w, $h);
-
-            # module may be installed, but e.g.
-            eval {
-                ($w, $h) = GetTerminalSize();
-            };
-
-            $width = $w if defined $w;
-        }
-
-        $width ||= 60;
-        $width -= 12;
-        $config->{terminal_width} = $width;
-    }
-
-    # jump out to build cache if requested
-    if(defined($config->{build})) {
-
-        if($config->{host} =~ /^(ensembl|useast)db\.ensembl\.org$/ && !defined($config->{admin})) {
-            die("ERROR: Cannot build cache using public database server ", $config->{host}, "\n");
-        }
-
-        # build the cache
-        debug("Building cache for ".$config->{species}) unless defined($config->{quiet});
-        build_full_cache($config);
-
-        # exit script
-        debug("Finished building cache") unless defined($config->{quiet});
-        exit(0);
-    }
-
-    # warn user DB will be used for SIFT/PolyPhen/Condel/HGVS/frequency
-    if(defined($config->{cache})) {
-
-        # these two def depend on DB
-        foreach my $param(grep {defined $config->{$_}} qw(hgvs check_frequency)) {
-            debug("INFO: Database will be accessed when using --$param") unless defined($config->{quiet});
-        }
-
-        # as does using HGVS or IDs as input
-        debug("INFO: Database will be accessed when using --format ", $config->{format}) if ($config->{format} eq 'id' || $config->{format} eq 'hgvs') && !defined($config->{quiet});
-
-        # the rest may be in the cache
-        foreach my $param(grep {defined $config->{$_}} qw(sift polyphen condel regulatory)) {
-            next if defined($config->{'cache_'.$param});
-            debug("INFO: Database will be accessed when using --$param; consider using the complete cache containing $param data (see documentation for details)") unless defined($config->{quiet});
-        }
-    }
-
-    # get list of chrs if supplied
-    if(defined($config->{chr})) {
-        my %chrs;
-
-        foreach my $val(split /\,/, $config->{chr}) {
-            my @nnn = split /\-/, $val;
-
-            foreach my $chr($nnn[0]..$nnn[-1]) {
-                $chrs{$chr} = 1;
-            }
-        }
-
-        $config->{chr} = \%chrs;
-    }
-
-    configure_plugins($config);
-
-    # get input file handle
-    $config->{in_file_handle} = &get_in_file_handle($config);
-
-    return $config;
-}
-
-# configures custom VEP plugins
-sub configure_plugins {
-
-    my $config = shift;
-
-    if (my @plugins = @{ $config->{plugin} }) {
-
-        $config->{plugin} = {};
-
-        # we turn config->{plugin} into a hash of plugin
-        # instances keyed by plugin name
-
-        use lib "$ENV{HOME}/.vep/Plugins";
-
-        for my $plugin (@plugins) {
-
-            # first check we can use the module
-
-            eval qq{
-                use $plugin;
-            };
-            if ($@) {
-                die "Failed to compile plugin $plugin: $@";
-            }
-
-            # now check we can instantiate it
-
-            my $instance;
-
-            eval {
-                $instance = $plugin->new($config);
-            };
-            if ($@) {
-                die "Failed to instantiate plugin $plugin: $@";
-            }
-
-            # check that the versions match
-
-            my $plugin_version = $instance->version if $instance->can('version');
-
-            my $version_ok = 1;
-
-            if ($plugin_version) {
-                my ($plugin_major, $plugin_minor, $plugin_maintenance) = split /\./, $plugin_version;
-                my ($major, $minor, $maintenance) = split /\./, $VERSION;
-
-                if ($plugin_major != $major) {
-                    warn "Warning: plugin '$plugin' version ($plugin_version) does not match the current VEP version ($VERSION).\n";
-                    $version_ok = 0;
-                }
-            }
-            else {
-                warn "Warning: plugin '$plugin' does not define a version number.\n";
-                $version_ok = 0;
-            }
-
-            warn "You may experience unexpected behaviour with this plugin.\n" unless $version_ok;
-
-            # and finally check that it implements all necessary methods
-
-            for my $required qw(run prefetch get_header_info check_feature_type) {
-                unless ($plugin->can($required)) {
-                    die "$plugin doesn't implement a required plugin method '$required', does it inherit from BaseVepPlugin?";
-                }
-            }
-
-            # all's good, so save the instance
-
-            $config->{plugin}->{$plugin} = $instance;
-
-            print "Using plugin: $plugin\n" if $config->{verbose};
-        }
-    }
-
-    else {
-        $config->{plugin} = {};
-    }
-}
-
-# connects to DBs; in standalone mode this just loads registry module
-sub connect_to_dbs {
-    my $config = shift;
-
-    # get registry
-    my $reg = 'Bio::EnsEMBL::Registry';
-
-    unless(defined($config->{standalone})) {
-        # load DB options from registry file if given
-        if(defined($config->{registry})) {
-            debug("Loading DB config from registry file ", $config->{registry}) unless defined($config->{quiet});
-            $reg->load_all(
-                $config->{registry},
-                $config->{verbose},
-                undef,
-                $config->{no_slice_cache}
-            );
-        }
-
-        # otherwise manually connect to DB server
-        else {
-            $reg->load_registry_from_db(
-                -host       => $config->{host},
-                -user       => $config->{user},
-                -pass       => $config->{password},
-                -port       => $config->{port},
-                -db_version => $config->{db_version},
-                -species    => $config->{species} =~ /^[a-z]+\_[a-z]+/i ? $config->{species} : undef,
-                -verbose    => $config->{verbose},
-                -no_cache   => $config->{no_slice_cache},
-            );
-        }
-
-        eval { $reg->set_reconnect_when_lost() };
-
-        if(defined($config->{verbose})) {
-            # get a meta container adaptors to check version
-            my $core_mca = $reg->get_adaptor($config->{species}, 'core', 'metacontainer');
-            my $var_mca = $reg->get_adaptor($config->{species}, 'variation', 'metacontainer');
-
-            if($core_mca && $var_mca) {
-                debug(
-                    "Connected to core version ", $core_mca->get_schema_version, " database ",
-                    "and variation version ", $var_mca->get_schema_version, " database"
-                );
-            }
-        }
-    }
-
-    return $reg;
-}
-
-# get adaptors from DB
-sub get_adaptors {
-    my $config = shift;
-
-    die "ERROR: No registry" unless defined $config->{reg};
-
-    $config->{vfa}   = $config->{reg}->get_adaptor($config->{species}, 'variation', 'variationfeature');
-    $config->{svfa}  = $config->{reg}->get_adaptor($config->{species}, 'variation', 'structuralvariationfeature');
-    $config->{tva}   = $config->{reg}->get_adaptor($config->{species}, 'variation', 'transcriptvariation');
-    $config->{pfpma} = $config->{reg}->get_adaptor($config->{species}, 'variation', 'proteinfunctionpredictionmatrix');
-    $config->{va}    = $config->{reg}->get_adaptor($config->{species}, 'variation', 'variation');
-
-    # get fake ones for species with no var DB
-    if(!defined($config->{vfa})) {
-        $config->{vfa}  = Bio::EnsEMBL::Variation::DBSQL::VariationFeatureAdaptor->new_fake($config->{species});
-        $config->{svfa} = Bio::EnsEMBL::Variation::DBSQL::StructuralVariationFeatureAdaptor->new_fake($config->{species});
-        $config->{tva}  = Bio::EnsEMBL::Variation::DBSQL::TranscriptVariationAdaptor->new_fake($config->{species});
-    }
-    else {
-        $config->{vfa}->db->include_failed_variations($config->{include_failed}) if defined($config->{vfa}->db) && $config->{vfa}->db->can('include_failed_variations');
-    }
-
-    $config->{sa}  = $config->{reg}->get_adaptor($config->{species}, $config->{core_type}, 'slice');
-    $config->{ga}  = $config->{reg}->get_adaptor($config->{species}, $config->{core_type}, 'gene');
-    $config->{ta}  = $config->{reg}->get_adaptor($config->{species}, $config->{core_type}, 'transcript');
-    $config->{mca} = $config->{reg}->get_adaptor($config->{species}, $config->{core_type}, 'metacontainer');
-    $config->{csa} = $config->{reg}->get_adaptor($config->{species}, $config->{core_type}, 'coordsystem');
-
-    # cache schema version
-    $config->{mca}->get_schema_version if defined $config->{mca};
-
-    # check we got slice adaptor - can't continue without a core DB
-    die("ERROR: Could not connect to core database\n") unless defined $config->{sa};
-}
-
-# gets regulatory adaptors
-sub get_reg_adaptors {
-    my $config = shift;
-
-    foreach my $type(@REG_FEAT_TYPES) {
-        next if defined($config->{$type.'_adaptor'});
-
-        my $adaptor = $config->{reg}->get_adaptor($config->{species}, 'funcgen', $type);
-        if(defined($adaptor)) {
-            $config->{$type.'_adaptor'} = $adaptor;
-        }
-        else {
-            delete $config->{regulatory};
-            last;
-        }
-    }
-}
-
-# gets file handle for input
-sub get_in_file_handle {
-    my $config = shift;
-
-    # define the filehandle to read input from
-    my $in_file_handle = new FileHandle;
-
-    if(defined($config->{input_file})) {
-
-        # check defined input file exists
-        die("ERROR: Could not find input file ", $config->{input_file}, "\n") unless -e $config->{input_file};
-
-        if($config->{input_file} =~ /\.gz$/){
-            $in_file_handle->open($config->{compress}." ". $config->{input_file} . " | " ) or die("ERROR: Could not read from input file ", $config->{input_file}, "\n");
-        }
-        else {
-            $in_file_handle->open( $config->{input_file} ) or die("ERROR: Could not read from input file ", $config->{input_file}, "\n");
-        }
-    }
-
-    # no file specified - try to read data off command line
-    else {
-        $in_file_handle = 'STDIN';
-        debug("Reading input from STDIN (or maybe you forgot to specify an input file?)...") unless defined $config->{quiet};
-    }
-
-    return $in_file_handle;
-}
-
-# gets file handle for output and adds header
-sub get_out_file_handle {
-    my $config = shift;
-
-    # define filehandle to write to
-    my $out_file_handle = new FileHandle;
-
-    # check if file exists
-    if(-e $config->{output_file} && !defined($config->{force_overwrite})) {
-        die("ERROR: Output file ", $config->{output_file}, " already exists. Specify a different output file with --output_file or overwrite existing file with --force_overwrite\n");
-    }
-
-    if($config->{output_file} =~ /stdout/i) {
-        $out_file_handle = *STDOUT;
-    }
-    else {
-        $out_file_handle->open(">".$config->{output_file}) or die("ERROR: Could not write to output file ", $config->{output_file}, "\n");
-    }
-
-    # define headers for a VCF file
-    my @vcf_headers = (
-        '#CHROM',
-        'POS',
-        'ID',
-        'REF',
-        'ALT',
-        'QUAL',
-        'FILTER',
-        'INFO'
-    );
-
-    # file conversion, don't want to add normal headers
-    if(defined($config->{convert})) {
-        # header for VCF
-        if($config->{convert} =~ /vcf/i) {
-            print $out_file_handle "##fileformat=VCFv4.0\n";
-            print $out_file_handle join "\t", @vcf_headers;
-            print $out_file_handle "\n";
-        }
-
-        return $out_file_handle;
-    }
-
-    # GVF output, no header
-    elsif(defined($config->{gvf}) || defined($config->{original})) {
-        print $out_file_handle join "\n", @{$config->{headers}} if defined($config->{headers}) && defined($config->{original});
-        return $out_file_handle;
-    }
-
-    elsif(defined($config->{vcf})) {
-
-        # create an info string for the VCF header
-        my @vcf_info_strings = ('##INFO=<ID=CSQ,Number=.,Type=String,Description="Consequence type as predicted by VEP">');
-
-        # add custom headers
-        foreach my $custom(@{$config->{custom}}) {
-            push @vcf_info_strings, '##INFO=<ID='.$custom->{name}.',Number=.,Type=String,Description="'.$custom->{file}.' ('.$custom->{type}.')">';
-        }
-
-        # plugin headers
-        my $plugin_header = get_plugin_headers($config);
-        if(defined($plugin_header)) {
-            $plugin_header =~ s/\n$//g;
-            push @vcf_info_strings, $plugin_header;
-        }
-
-        # if this is already a VCF file, we need to add extra headers in the right place
-        if(defined($config->{headers})) {
-
-            for my $i(0..$#{$config->{headers}}) {
-                if($config->{headers}->[$i] =~ /^\#CHROM\s+POS\s+ID/) {
-                    splice(@{$config->{headers}}, $i, 0, @vcf_info_strings);
-                }
-            }
-
-            print $out_file_handle join "\n", @{$config->{headers}};
-            print $out_file_handle "\n";
-        }
-
-        else {
-            print $out_file_handle "##fileformat=VCFv4.0\n";
-            print $out_file_handle join "\n", @vcf_info_strings;
-            print $out_file_handle "\n";
-            print $out_file_handle join "\t", @vcf_headers;
-            print $out_file_handle "\n";
-        }
-
-        return $out_file_handle;
-    }
-
-    # make header
-    my $time = &get_time;
-    my $db_string = $config->{mca}->dbc->dbname." on ".$config->{mca}->dbc->host if defined $config->{mca};
-    $db_string .= "\n## Using cache in ".$config->{dir} if defined($config->{cache});
-    my $version_string =
-        "Using API version ".$config->{reg}->software_version.
-        ", DB version ".(defined $config->{mca} && $config->{mca}->get_schema_version ? $config->{mca}->get_schema_version : '?');
-
-    my $header =<<HEAD;
-## ENSEMBL VARIANT EFFECT PREDICTOR v$VERSION
-## Output produced at $time
-## Connected to $db_string
-## $version_string
-## Extra column keys:
-## CANONICAL    : Indicates if transcript is canonical for this gene
-## CCDS         : Indicates if transcript is a CCDS transcript
-## HGNC         : HGNC gene identifier
-## ENSP         : Ensembl protein identifer
-## HGVSc        : HGVS coding sequence name
-## HGVSp        : HGVS protein sequence name
-## SIFT         : SIFT prediction
-## PolyPhen     : PolyPhen prediction
-## Condel       : Condel SIFT/PolyPhen consensus prediction
-## MATRIX       : The source and identifier of a transcription factor binding profile aligned at this position
-## HIGH_INF_POS : A flag indicating if the variant falls in a high information position of a transcription factor binding profile
-HEAD
-
-    $header .= get_plugin_headers($config);
-
-    # add headers
-    print $out_file_handle $header;
-
-    # add custom data defs
-    if(defined($config->{custom})) {
-        foreach my $custom(@{$config->{custom}}) {
-            print $out_file_handle '## '.$custom->{name}."\t: ".$custom->{file}.' ('.$custom->{type}.")\n";
-        }
-    }
-
-    # add column headers
-    print $out_file_handle '#', (join "\t", @OUTPUT_COLS);
-    print $out_file_handle "\n";
-
-    return $out_file_handle;
-}
-
-sub get_plugin_headers {
-
-    my $config = shift;
-
-    my $header = "";
-
-    for my $plugin (values %{ $config->{plugin} }) {
-        if (my $hdr = $plugin->get_header_info) {
-            for my $key (keys %$hdr) {
-                my $val = $hdr->{$key};
-
-                if($config->{vcf}) {
-                    $header .= '##INFO=<ID='.$key.',Number=.,Type=String,Description="'.$val.'">\n';
-                }
-                else {
-                    $header .= "## $key\t: $val\n";
-                }
-            }
-        }
-    }
-
-    return $header;
-}
-
-# convert a variation feature to a line of output
-sub convert_vf {
-    my $config = shift;
-    my $vf = shift;
-
-    my $convert_method = 'convert_to_'.lc($config->{convert});
-    my $method_ref   = \&$convert_method;
-
-    my $line = &$method_ref($config, $vf);
-    my $handle = $config->{out_file_handle};
-
-    if(scalar @$line) {
-        print $handle join "\t", @$line;
-        print $handle "\n";
-    }
-}
-
-# converts to Ensembl format
-sub convert_to_ensembl {
-    my $config = shift;
-    my $vf = shift;
-
-    return [
-        $vf->{chr} || $vf->seq_region_name,
-        $vf->start,
-        $vf->end,
-        $vf->allele_string,
-        $vf->strand,
-        $vf->variation_name
-    ];
-}
-
-
-# converts to pileup format
-sub convert_to_pileup {
-    my $config = shift;
-    my $vf = shift;
-
-    # look for imbalance in the allele string
-    my %allele_lengths;
-    my @alleles = split /\//, $vf->allele_string;
-
-    foreach my $allele(@alleles) {
-        $allele =~ s/\-//g;
-        $allele_lengths{length($allele)} = 1;
-    }
-
-    # in/del
-    if(scalar keys %allele_lengths > 1) {
-
-        if($vf->allele_string =~ /\-/) {
-
-            # insertion?
-            if($alleles[0] eq '-') {
-                shift @alleles;
-
-                for my $i(0..$#alleles) {
-                    $alleles[$i] =~ s/\-//g;
-                    $alleles[$i] = '+'.$alleles[$i];
-                }
-            }
-
-            else {
-                @alleles = grep {$_ ne '-'} @alleles;
-
-                for my $i(0..$#alleles) {
-                    $alleles[$i] =~ s/\-//g;
-                    $alleles[$i] = '-'.$alleles[$i];
-                }
-            }
-
-            @alleles = grep {$_ ne '-' && $_ ne '+'} @alleles;
-
-            return [
-                $vf->{chr} || $vf->seq_region_name,
-                $vf->start - 1,
-                '*',
-                (join "/", @alleles),
-            ];
-        }
-
-        else {
-            warn "WARNING: Unable to convert variant to pileup format on line number ", $config->{line_number} unless defined($config->{quiet});
-            return [];
-        }
-
-    }
-
-    # balanced sub
-    else {
-        return [
-            $vf->{chr} || $vf->seq_region_name,
-            $vf->start,
-            shift @alleles,
-            (join "/", @alleles),
-        ];
-    }
-}
-
-# prints a line of output from the hash
-sub print_line {
-    my $config = shift;
-    my $line = shift;
-    return unless defined($line);
-
-    my $output;
-
-    # normal
-    if(ref($line) eq 'HASH') {
-        $line->{Extra} = join ';', map { $_.'='.$line->{Extra}->{$_} } keys %{ $line->{Extra} || {} };
-        $output = join "\t", map { $line->{$_} || '-' } @OUTPUT_COLS;
-    }
-
-    # gvf
-    else {
-        $output = $line;
-    }
-
-    my $fh = $config->{out_file_handle};
-    print $fh "$output\n";
-}
-
-# outputs usage message
-sub usage {
-    my $usage =<<END;
-#----------------------------------#
-# ENSEMBL VARIANT EFFECT PREDICTOR #
-#----------------------------------#
-
-version $VERSION
-
-By Will McLaren (wm2\@ebi.ac.uk)
-
-http://www.ensembl.org/info/docs/variation/vep/vep_script.html
-
-Usage:
-perl variant_effect_predictor.pl [arguments]
-
-Options
-=======
-
---help                 Display this message and quit
---verbose              Display verbose output as the script runs [default: off]
---quiet                Suppress status and warning messages [default: off]
---no_progress          Suppress progress bars [default: off]
-
---config               Load configuration from file. Any command line options
-                       specified overwrite those in the file [default: off]
-
--i | --input_file      Input file - if not specified, reads from STDIN. Files
-                       may be gzip compressed.
---format               Specify input file format - one of "ensembl", "pileup",
-                       "vcf", "hgvs", "id" or "guess" to try and work out format.
--o | --output_file     Output file. Write to STDOUT by specifying -o STDOUT - this
-                       will force --quiet [default: "variant_effect_output.txt"]
---force_overwrite      Force overwriting of output file [default: quit if file
-                       exists]
---original             Writes output as it was in input - must be used with --filter
-                       [default: off]
---vcf                  Write output as VCF (forces --summary due to limit of one
-                       variant per line, you may also specify --most_severe to print
-                       only most severe consequence per variant) [default: off]
---gvf                  Write output as GVF [default: off]
-
---species [species]    Species to use [default: "human"]
-
--t | --terms           Type of consequence terms to output - one of "ensembl", "SO",
-                       "NCBI" [default: ensembl]
-
---sift=[p|s|b]         Add SIFT [p]rediction, [s]core or [b]oth [default: off]
---polyphen=[p|s|b]     Add PolyPhen [p]rediction, [s]core or [b]oth [default: off]
---condel=[p|s|b]       Add Condel SIFT/PolyPhen consensus [p]rediction, [s]core or
-                       [b]oth. Add 1 (e.g. b1) to option to use old Condel algorithm
-                       [default: off]
-
-NB: SIFT, PolyPhen and Condel predictions are currently available for human only
-
---regulatory           Look for overlaps with regulatory regions. The script can
-                       also call if a variant falls in a high information position
-                       within a transcription factor binding site. Output lines have
-                       a Feature type of RegulatoryFeature or MotifFeature
-                       [default: off]
-
-NB: Regulatory consequences are currently available for human and mouse only
-
---custom [file list]   Add custom annotations from tabix-indexed files. See
-                       documentation for full details [default: off]
---hgnc                 Add HGNC gene identifiers to output [default: off]
---hgvs                 Output HGVS identifiers (coding and protein). Requires database
-                       connection [default: off]
---ccds                 Output CCDS transcript identifiers [default: off]
---xref_refseq          Output aligned RefSeq mRNA identifier for transcript. NB: the
-                       RefSeq and Ensembl transcripts aligned in this way MAY NOT, AND
-                       FREQUENCTLY WILL NOT, match exactly in sequence, exon structure
-                       and protein product [default: off]
---protein              Output Ensembl protein identifer [default: off]
---gene                 Force output of Ensembl gene identifer - disabled by default
-                       unless using --cache or --no_whole_genome [default: off]
---canonical            Indicate if the transcript for this consequence is the canonical
-                       transcript for this gene [default: off]
-
---no_intergenic        Excludes intergenic consequences from the output [default: off]
---coding_only          Only return consequences that fall in the coding region of
-                       transcripts [default: off]
---most_severe          Ouptut only the most severe consequence per variation.
-                       Transcript-specific columns will be left blank. [default: off]
---summary              Output only a comma-separated list of all consequences per
-                       variation. Transcript-specific columns will be left blank.
-                       [default: off]
---per_gene             Output only the most severe consequence per gene. Where more
-                       than one transcript has the same consequence, the transcript
-                       chosen is arbitrary. [default: off]
-
-
---check_ref            If specified, checks supplied reference allele against stored
-                       entry in Ensembl Core database [default: off]
---check_existing       If specified, checks for existing co-located variations in the
-                       Ensembl Variation database [default: off]
---check_alleles        If specified, the alleles of existing co-located variations
-                       are compared to the input; an existing variation will only
-                       be reported if no novel allele is in the input (strand is
-                       accounted for) [default: off]
-
---filter [filters]     Filter output by consequence type. Use this to output only
-                       variants that have at least one consequence type matching the
-                       filter. Multiple filters can be used separated by ",". By
-                       combining this with --original it is possible to run the VEP
-                       iteratively to progressively filter a set of variants. See
-                       documentation for full details [default: off]
-
---check_frequency      Turns on frequency filtering. Use this to include or exclude
-                       variants based on the frequency of co-located existing
-                       variants in the Ensembl Variation database. You must also
-                       specify all of the following --freq flags [default: off]
---freq_pop [pop]       Name of the population to use e.g. hapmap_ceu for CEU HapMap,
-                       1kg_yri for YRI 1000 genomes. See documentation for more
-                       details
---freq_freq [freq]     Frequency to use in filter. Must be a number between 0 and 0.5
---freq_gt_lt [gt|lt]   Specify whether the frequency should be greater than (gt) or
-                       less than (lt) --freq_freq
---freq_filter          Specify whether variants that pass the above should be included
-  [exclude|include]    or excluded from analysis
-
---chr [list]           Select a subset of chromosomes to analyse from your file. Any
-                       data not on this chromosome in the input will be skipped. The
-                       list can be comma separated, with "-" characters representing
-                       a range e.g. 1-5,8,15,X [default: off]
---gp                   If specified, tries to read GRCh37 position from GP field in the
-                       INFO column of a VCF file. Only applies when VCF is the input
-                       format and human is the species [default: off]
-
---convert              Convert the input file to the output format specified.
-  [ensembl|vcf|pileup] Converted output is written to the file specified in
-                       --output_file. No consequence calculation is carried out when
-                       doing file conversion. [default: off]
-
---refseq               Use the otherfeatures database to retrieve transcripts - this
-                       database contains RefSeq transcripts (as well as CCDS and
-                       Ensembl EST alignments) [default: off]
---host                 Manually define database host [default: "ensembldb.ensembl.org"]
--u | --user            Database username [default: "anonymous"]
---port                 Database port [default: 5306]
---password             Database password [default: no password]
---genomes              Sets DB connection params for Ensembl Genomes [default: off]
---registry             Registry file to use defines DB connections [default: off]
-                       Defining a registry file overrides above connection settings.
---db_version=[number]  Force script to load DBs from a specific Ensembl version. Not
-                       advised due to likely incompatibilities between API and DB
-
---no_whole_genome      Run in old-style, non-whole genome mode [default: off]
---buffer_size          Sets the number of variants sent in each batch [default: 5000]
-                       Increasing buffer size can retrieve results more quickly
-                       but requires more memory. Only applies to whole genome mode.
-
---cache                Enables read-only use of cache [default: off]
---dir [directory]      Specify the base cache directory to use [default: "\$HOME/.vep/"]
---write_cache          Enable writing to cache [default: off]
---build [all|list]     Build a complete cache for the selected species. Build for all
-                       chromosomes with --build all, or a list of chromosomes (see
-                       --chr). DO NOT USE WHEN CONNECTED TO PUBLIC DB SERVERS AS THIS
-                       VIOLATES OUR FAIR USAGE POLICY [default: off]
-
---compress             Specify utility to decompress cache files - may be "gzcat" or
-                       "gzip -dc" Only use if default does not work [default: zcat]
-
---skip_db_check        ADVANCED! Force the script to use a cache built from a different
-                       database than specified with --host. Only use this if you are
-                       sure the hosts are compatible (e.g. ensembldb.ensembl.org and
-                       useastdb.ensembl.org) [default: off]
---cache_region_size    ADVANCED! The size in base-pairs of the region covered by one
-                       file in the cache. [default: 1MB]
-END
-
-    print $usage;
-}
--- a/variant_effect_predictor/.#variant_effect_predictor.pl.1.17	Fri Aug 03 10:04:48 2012 -0400
+++ /dev/null	Thu Jan 01 00:00:00 1970 +0000
@@ -1,2537 +0,0 @@
-#!/usr/bin/perl
-
-=head1 LICENSE
-
-  Copyright (c) 1999-2011 The European Bioinformatics Institute and
-  Genome Research Limited.  All rights reserved.
-
-  This software is distributed under a modified Apache license.
-  For license details, please see
-
-    http://www.ensembl.org/info/about/code_licence.html
-
-=head1 CONTACT
-
-  Please email comments or questions to the public Ensembl
-  developers list at <ensembl-dev@ebi.ac.uk>.
-
-  Questions may also be sent to the Ensembl help desk at
-  <helpdesk@ensembl.org>.
-
-=cut
-
-=head1 NAME
-
-Variant Effect Predictor - a script to predict the consequences of genomic variants
-
-http://www.ensembl.org/info/docs/variation/vep/vep_script.html
-
-Version 2.1
-
-by Will McLaren (wm2@ebi.ac.uk)
-=cut
-
-use strict;
-use Getopt::Long;
-use FileHandle;
-use Bio::EnsEMBL::Registry;
-use Bio::EnsEMBL::Variation::DBSQL::VariationFeatureAdaptor;
-use Bio::EnsEMBL::Variation::Utils::VariationEffect qw(MAX_DISTANCE_FROM_TRANSCRIPT);
-use Bio::EnsEMBL::Utils::Sequence qw(reverse_comp);
-use Bio::EnsEMBL::Variation::Utils::Sequence qw(unambiguity_code);
-use Storable qw(nstore_fd fd_retrieve);
-
-# we need to manually include all these modules for caching to work
-use Bio::EnsEMBL::CoordSystem;
-use Bio::EnsEMBL::Transcript;
-use Bio::EnsEMBL::Translation;
-use Bio::EnsEMBL::Exon;
-use Bio::EnsEMBL::DBSQL::GeneAdaptor;
-use Bio::EnsEMBL::DBSQL::SliceAdaptor;
-use Bio::EnsEMBL::DBSQL::TranslationAdaptor;
-use Bio::EnsEMBL::DBSQL::TranscriptAdaptor;
-use Bio::EnsEMBL::DBSQL::MetaContainer;
-use Bio::EnsEMBL::DBSQL::CoordSystemAdaptor;
-
-
-# debug
-#use Time::HiRes qw(tv_interval gettimeofday);
-
-# output columns
-my @OUTPUT_COLS = qw(
-    Uploaded_variation
-    Location
-    Allele
-    Gene
-    Feature
-    Feature_type
-    Consequence
-    cDNA_position
-    CDS_position
-    Protein_position
-    Amino_acids
-    Codons
-    Existing_variation
-    Extra
-);
-
-# global vars
-my $VERSION = '2.1';
-
-# set output autoflush for progress bars
-$| = 1;
-
-# configure from command line opts
-my $config = &configure(scalar @ARGV);
-
-# run the main sub routine
-&main($config);
-
-# this is the main sub-routine - it needs the configured $config hash
-sub main {
-    my $config = shift;
-
-    debug("Starting...") unless defined $config->{quiet};
-
-    my ($include_regions, $transcript_cache);
-
-    # scan file if requested
-    $include_regions = &scan_file($config) if defined($config->{scan});
-
-    # build transcript cache upfront if requested
-    $transcript_cache = &cache_transcripts($config, $include_regions) if defined($config->{upfront});
-
-    # create a hash to hold slices so we don't get the same one twice
-    my %slice_cache = ();
-
-    # load slices from the transcript cache if we have it
-    # saves us fetching them again
-    %slice_cache = %{&build_slice_cache($config, $transcript_cache)} if defined($transcript_cache);
-
-    my @new_vfs;
-    my %vf_hash;
-
-    my $line_number = 0;
-    my ($vf_count, $total_vf_count);
-    my $in_file_handle = $config->{in_file_handle};
-
-    # read the file
-    while(<$in_file_handle>) {
-      chomp;
-
-      $line_number++;
-
-      # header line?
-      next if /^\#/;
-
-      # some lines (pileup) may actually parse out into more than one variant
-      foreach my $sub_line(@{&parse_line($config, $_)}) {
-
-        # get the sub-line into named variables
-        my ($chr, $start, $end, $allele_string, $strand, $var_name) = @{$sub_line};
-
-        next if defined($config->{chr}) && !$config->{chr}->{$chr};
-
-        # non-variant line from VCF
-        next if $chr eq 'non-variant';
-
-        # fix inputs
-        $chr =~ s/chr//ig unless $chr =~ /^chromosome$/i;
-        $chr = 'MT' if $chr eq 'M';
-        $strand = ($strand =~ /\-/ ? "-1" : "1");
-        $allele_string =~ tr/acgt/ACGT/;
-
-        # sanity checks
-        unless($start =~ /^\d+$/ && $end =~ /^\d+$/) {
-          warn("WARNING: Start $start or end $end coordinate invalid on line $line_number\n") unless defined $config->{quiet};
-          next;
-        }
-
-        unless($allele_string =~ /([ACGT-]+\/*)+/) {
-          warn("WARNING: Invalid allele string $allele_string on line $line_number\n") unless defined $config->{quiet};
-          next;
-        }
-
-        # now get the slice
-        my $slice;
-
-        # don't get slices if we're using cache
-        # we can steal them from transcript objects later
-        if((!defined($config->{cache}) && !defined($config->{whole_genome})) || defined($config->{check_ref})) {
-
-            # check if we have fetched this slice already
-            if(defined $slice_cache{$chr}) {
-                $slice = $slice_cache{$chr};
-            }
-
-            # if not create a new one
-            else {
-
-                $slice = &get_slice($config, $chr);
-
-                # if failed, warn and skip this line
-                if(!defined($slice)) {
-                    warn("WARNING: Could not fetch slice named $chr on line $line_number\n") unless defined $config->{quiet};
-                    next;
-                }
-
-                # store the hash
-                $slice_cache{$chr} = $slice;
-            }
-        }
-
-        # check reference allele if requested
-        if(defined $config->{check_ref}) {
-            my $ref_allele = (split /\//, $allele_string)[0];
-
-            my $ok = 0;
-            my $slice_ref_allele;
-
-            # insertion, therefore no ref allele to check
-            if($ref_allele eq '-') {
-                $ok = 1;
-            }
-            else {
-                my $slice_ref = $slice->sub_Slice($start, $end, $strand);
-
-                if(!defined($slice_ref)) {
-                    warn "WARNING: Could not fetch sub-slice from $start\-$end\($strand\) on line $line_number" unless defined $config->{quiet};
-                }
-
-                else {
-                    $slice_ref_allele = $slice_ref->seq;
-                    $ok = ($slice_ref_allele eq $ref_allele ? 1 : 0);
-                }
-            }
-
-            if(!$ok) {
-                warn
-                    "WARNING: Specified reference allele $ref_allele ",
-                    "does not match Ensembl reference allele",
-                    ($slice_ref_allele ? " $slice_ref_allele" : ""),
-                    " on line $line_number" unless defined $config->{quiet};
-                next;
-            }
-        }
-
-        # create a new VariationFeature object
-        my $new_vf = Bio::EnsEMBL::Variation::VariationFeature->new(
-          -start => $start,
-          -end => $end,
-          -slice => $slice,           # the variation must be attached to a slice
-          -allele_string => $allele_string,
-          -strand => $strand,
-          -map_weight => 1,
-          -adaptor => $config->{vfa},           # we must attach a variation feature adaptor
-          -variation_name => (defined $var_name ? $var_name : $chr.'_'.$start.'_'.$allele_string),
-        );
-
-        if(defined $config->{whole_genome}) {
-            push @{$vf_hash{$chr}{int($start / $config->{chunk_size})}{$start}}, $new_vf;
-            $vf_count++;
-            $total_vf_count++;
-
-            if($vf_count == $config->{buffer_size}) {
-                debug("Read $vf_count variants into buffer") unless defined($config->{quiet});
-
-                $include_regions ||= &regions_from_hash($config, \%vf_hash);
-
-                &check_existing_hash($config, \%vf_hash) if defined($config->{check_existing});
-                &whole_genome_fetch($config, \%vf_hash, $transcript_cache, $include_regions);
-
-                debug("Processed $total_vf_count total variants") unless defined($config->{quiet});
-
-                undef $include_regions unless defined($config->{scan});
-                %vf_hash = ();
-                $vf_count = 0;
-            }
-        }
-        else {
-            &print_consequences($config, [$new_vf]);
-            $vf_count++;
-            $total_vf_count++;
-            debug("Processed $vf_count variants") if $vf_count =~ /0$/ && defined($config->{verbose});
-        }
-      }
-    }
-
-    # if in whole-genome mode, finish off the rest of the buffer
-    if(defined $config->{whole_genome} && %vf_hash) {
-        debug("Read $vf_count variants into buffer") unless defined($config->{quiet});
-        $include_regions ||= &regions_from_hash($config, \%vf_hash);
-        &check_existing_hash($config, \%vf_hash) if defined($config->{check_existing});
-        &whole_genome_fetch($config, \%vf_hash, $transcript_cache, $include_regions);
-    }
-
-    debug("Executed ", defined($Bio::EnsEMBL::DBSQL::StatementHandle::count_queries) ? $Bio::EnsEMBL::DBSQL::StatementHandle::count_queries : 'unknown number of', " SQL statements") if defined($config->{count_queries}) && !defined($config->{quiet});
-
-    debug("Finished!") unless defined $config->{quiet};
-}
-
-# takes a listref of variation features and prints out consequence information
-sub print_consequences {
-    my $config = shift;
-    my $vfs = shift;
-
-    my $out_file_handle = $config->{out_file_handle};
-
-    # method name for consequence terms
-    my $term_method = $config->{terms}.'_term';
-
-    my ($vf_count, $vf_counter);
-    $vf_count = scalar @$vfs;
-    my $new_vf;
-
-    while($new_vf = shift @$vfs) {
-
-        &progress($config, $vf_counter++, $vf_count) unless $vf_count == 1;
-
-        # find any co-located existing VFs
-        my $existing_vf = $new_vf->{existing};
-        $existing_vf ||= &find_existing($config, $new_vf) if defined $config->{check_existing};
-
-        # initiate line hash for this variation
-        my $line = {
-            Uploaded_variation  => $new_vf->variation_name,
-            Location            => $new_vf->seq_region_name.':'.&format_coords($new_vf->start, $new_vf->end),
-            Existing_variation  => $existing_vf,
-            Extra               => {},
-        };
-
-        # force empty hash into object's transcript_variations if undefined from whole_genome_fetch
-        # this will stop the API trying to go off and fill it again
-        $new_vf->{transcript_variations} ||= {} if defined $config->{whole_genome};
-
-        # regulatory stuff
-        if(!defined $config->{coding_only} && defined $config->{regulatory}) {
-
-            for my $rfv (@{ $new_vf->get_all_RegulatoryFeatureVariations }) {
-
-                my $rf = $rfv->regulatory_feature;
-
-                $line->{Feature_type}   = 'RegulatoryFeature';
-                $line->{Feature}        = $rf->stable_id;
-
-                # this currently always returns 'RegulatoryFeature', so we ignore it for now
-                #$line->{Extra}->{REG_FEAT_TYPE} = $rf->feature_type->name;
-
-                for my $rfva (@{ $rfv->get_all_alternate_RegulatoryFeatureVariationAlleles }) {
-
-                    $line->{Allele}         = $rfva->variation_feature_seq;
-                    $line->{Consequence}    = join ',',
-                        map { $_->$term_method || $_->display_term }
-                            @{ $rfva->get_all_OverlapConsequences };
-
-                    print_line($line);
-                }
-            }
-
-            for my $mfv (@{ $new_vf->get_all_MotifFeatureVariations }) {
-
-                my $mf = $mfv->motif_feature;
-
-                $line->{Feature_type}   = 'MotifFeature';
-                $line->{Feature}        = $mf->binding_matrix->name;
-
-                for my $mfva (@{ $mfv->get_all_alternate_MotifFeatureVariationAlleles }) {
-
-                    $line->{Extra}->{MATRIX} = $mf->binding_matrix->description.'_'.$mf->display_label,
-                    $line->{Extra}->{MATRIX} =~ s/\s+/\_/g;
-
-                    my $high_inf_pos = $mfva->in_informative_position;
-
-                    if (defined $high_inf_pos) {
-                        $line->{Extra}->{HIGH_INF_POS}  = ($high_inf_pos ? 'Y' : 'N');
-                    }
-
-                    $line->{Allele}         = $mfva->variation_feature_seq;
-                    $line->{Consequence}    = join ',',
-                        map { $_->$term_method || $_->display_term }
-                            @{ $mfva->get_all_OverlapConsequences };
-
-                    print_line($line);
-                }
-            }
-        }
-
-
-        # get TVs
-        my $tvs = $new_vf->get_all_TranscriptVariations;
-
-        # no TVs (intergenic) or only most severe
-        if(!@$tvs || defined($config->{most_severe}) || defined($config->{summary})) {
-            if(defined($config->{summary})) {
-                $line->{Consequence} = join ",", @{$new_vf->consequence_type($config->{terms}) || $new_vf->consequence_type};
-            }
-            else {
-                $line->{Consequence} = $new_vf->display_consequence($config->{terms}) || $new_vf->display_consequence;
-            }
-
-            &print_line($line);
-        }
-
-        else {
-            foreach my $tv(@$tvs) {
-
-                next if(defined $config->{coding_only} && !($tv->affects_transcript));
-
-                my $t = $tv->transcript;
-
-                $line->{Feature_type}       = 'Transcript';
-                $line->{Feature}            = $t->stable_id if defined $t;
-                $line->{cDNA_position}      = &format_coords($tv->cdna_start, $tv->cdna_end);
-                $line->{CDS_position}       = &format_coords($tv->cds_start, $tv->cds_end);
-                $line->{Protein_position}   = &format_coords($tv->translation_start, $tv->translation_end);
-
-                # get gene
-                my $gene;
-
-                if(defined($config->{gene})) {
-                    $line->{Gene} = $tv->transcript->{_gene_stable_id};
-
-                    if(!defined($line->{Gene})) {
-                        $gene = $config->{ga}->fetch_by_transcript_stable_id($t->stable_id);
-                        $line->{Gene}= $gene->stable_id;
-                    }
-                }
-
-                foreach my $tva(@{$tv->get_all_alternate_TranscriptVariationAlleles}) {
-
-                    # basic stuff
-                    $line->{Allele}         = $tva->variation_feature_seq;
-                    $line->{Amino_acids}    = $tva->pep_allele_string;
-                    $line->{Codons}         = $tva->display_codon_allele_string;
-                    $line->{Consequence}    = join ",", map {$_->$term_method || $_->display_term} @{$tva->get_all_OverlapConsequences};
-
-                    # HGNC
-                    if(defined $config->{hgnc}) {
-                        my $hgnc;
-                        $hgnc = $tv->transcript->{_gene_hgnc};
-
-                        if(!defined($hgnc)) {
-                            if(!defined($gene)) {
-                                $gene = $config->{ga}->fetch_by_transcript_stable_id($tv->transcript->stable_id);
-                            }
-
-                            my @entries = grep {$_->database eq 'HGNC'} @{$gene->get_all_DBEntries()};
-                            if(scalar @entries) {
-                                $hgnc = $entries[0]->display_id;
-                            }
-                        }
-
-                        $hgnc = undef if $hgnc eq '-';
-
-                        $line->{Extra}->{HGNC} = $hgnc if defined($hgnc);
-                    }
-
-                    # protein ID
-                    if(defined $config->{protein} && $t->translation) {
-                        $line->{Extra}->{ENSP} = $t->translation->stable_id;
-                    }
-
-                    # HGVS
-                    if(defined $config->{hgvs}) {
-                        $line->{Extra}->{HGVSc} = $tva->hgvs_coding if defined($tva->hgvs_coding);
-                        $line->{Extra}->{HGVSp} = $tva->hgvs_protein if defined($tva->hgvs_protein);
-                    }
-
-                    foreach my $tool (qw(SIFT PolyPhen Condel)) {
-                        my $lc_tool = lc($tool);
-
-                        if (my $opt = $config->{$lc_tool}) {
-                            my $want_pred   = $opt =~ /^p/i;
-                            my $want_score  = $opt =~ /^s/i;
-                            my $want_both   = $opt =~ /^b/i;
-
-                            if ($want_both) {
-                                $want_pred  = 1;
-                                $want_score = 1;
-                            }
-
-                            next unless $want_pred || $want_score;
-
-                            my $pred_meth   = $lc_tool.'_prediction';
-                            my $score_meth  = $lc_tool.'_score';
-
-                            my $pred = $tva->$pred_meth;
-
-                            if($pred) {
-
-                                if ($want_pred) {
-                                    $pred =~ s/\s+/\_/;
-                                    $line->{Extra}->{$tool} = $pred;
-                                }
-
-                                if ($want_score) {
-                                    my $score = $tva->$score_meth;
-
-                                    if(defined $score) {
-                                        if($want_pred) {
-                                            $line->{Extra}->{$tool} .= "($score)";
-                                        }
-                                        else {
-                                            $line->{Extra}->{$tool} = $score;
-                                        }
-                                    }
-                                }
-                            }
-                        }
-                    }
-
-                    &print_line($line);
-                }
-            }
-        }
-    }
-
-    &end_progress($config) unless $vf_count == 1;
-}
-
-# prints a line from the hash
-sub print_line {
-    my $line = shift;
-
-    $line->{Extra} = join ';', map { $_.'='.$line->{Extra}->{$_} } keys %{ $line->{Extra} || {} };
-
-    my $output = join "\t", map { $line->{$_} || '-' } @OUTPUT_COLS;
-
-    my $fh = $config->{out_file_handle};
-
-    print $fh "$output\n";
-
-    # clear out the Extra column for the next line
-    $line->{Extra} = {};
-}
-
-# sets up configuration hash that is used throughout the script
-sub configure {
-    my $args = shift;
-
-    my $config = {};
-
-    GetOptions(
-        $config,
-        'help',                    # displays help message
-
-        # input options,
-        'config=s',                # config file name
-        'input_file=s',            # input file name
-        'format=s',                # input file format
-
-        # DB options
-        'species=s',               # species e.g. human, homo_sapiens
-        'registry=s',              # registry file
-        'host=s',                  # database host
-        'port=s',                  # database port
-        'user=s',                  # database user name
-        'password=s',              # database password
-        'db_version=i',            # Ensembl database version to use e.g. 62
-        'genomes',                 # automatically sets DB params for e!Genomes
-        #'no_disconnect',           # disables disconnect_when_inactive
-
-        # runtime options
-        'most_severe',             # only return most severe consequence
-        'summary',                 # only return one line per variation with all consquence types
-        'buffer_size=i',           # number of variations to read in before analysis
-        'chunk_size=s',            # size in bases of "chunks" used in internal hash structure
-        'check_ref',               # check supplied reference allele against DB
-        'check_existing',          # find existing co-located variations
-        'check_alleles',           # only attribute co-located if alleles are the same
-        'failed=i',                # include failed variations when finding existing
-        'no_whole_genome',         # disables now default whole-genome mode
-        'whole_genome',            # proxy for whole genome mode - now just warns user
-        'gp',                      # read coords from GP part of INFO column in VCF (probably only relevant to 1KG)
-        'chr=s',                   # analyse only these chromosomes, e.g. 1-5,10,MT
-
-        # verbosity options
-        'verbose',                 # print out a bit more info while running
-        'quiet',                   # print nothing to STDOUT (unless using -o stdout)
-        'no_progress',             # don't display progress bars
-
-        # output options
-        'output_file=s',           # output file name
-        'force_overwrite',         # force overwrite of output file if already exists
-        'terms=s',                 # consequence terms to use e.g. NCBI, SO
-        'coding_only',             # only return results for consequences in coding regions
-        'protein',                 # add e! protein ID to extra column
-        'hgnc',                    # add HGNC gene ID to extra column
-        'hgvs',                    # add HGVS names to extra column
-        'sift=s',                  # SIFT predictions
-        'polyphen=s',              # PolyPhen predictions
-        'condel=s',                # Condel predictions
-        'gene',                    # force gene column to be populated (disabled by default, enabled when using cache)
-        'regulatory',              # enable regulatory stuff
-
-        # cache stuff
-        'cache',                   # use cache
-        'write_cache',             # enables writing to the cache
-        'build=s',                 # builds cache from DB from scratch; arg is either all (all top-level seqs) or a list of chrs
-        'scan',                    # scan the whole input file at the beginning to get regions
-        'upfront',                 # fetch transcripts and prefetch upfront before analysis starts (requires scan)
-        'prefetch',                # prefetch exons, translation, introns, codon table etc for each transcript
-        'strip',                   # strips adaptors etc from objects before caching them
-        'rebuild=s',               # rebuilds cache by reading in existing then redumping - probably don't need to use this any more
-        'dir=s',                   # dir where cache is found (defaults to $HOME/.vep/)
-        'cache_region_size=i',     # size of region in bases for each cache file
-        'no_slice_cache',          # tell API not to cache features on slice
-        'standalone',              # standalone mode uses minimal set of modules installed in same dir, no DB connection
-        'skip_db_check',           # don't compare DB parameters with cached
-        'compress=s',              # by default we use zcat to decompress; user may want to specify gzcat or "gzip -dc"
-
-        # debug
-        'cluck',                   # these two need some mods to Bio::EnsEMBL::DBSQL::StatementHandle to work. Clucks callback trace and SQL
-        'count_queries',           # counts SQL queries executed
-    );
-
-    # print usage message if requested or no args supplied
-    if(defined($config->{help}) || !$args) {
-        &usage;
-        exit(0);
-    }
-
-    # config file?
-    if(defined $config->{config}) {
-
-        open CONFIG, $config->{config} or die "ERROR: Could not open config file \"".$config->{config}."\"\n";
-
-        while(<CONFIG>) {
-            next if /^\#/;
-            my ($key, $value) = split /\s+|\=/;
-            $key =~ s/^\-//g;
-            $config->{$key} = $value unless defined $config->{$key};
-        }
-
-        close CONFIG;
-    }
-
-    # can't be both quiet and verbose
-    die "ERROR: Can't be both quiet and verbose!" if defined($config->{quiet}) && defined($config->{verbose});
-
-    # check file format
-    if(defined $config->{format}) {
-        die "ERROR: Unrecognised input format specified \"".$config->{format}."\"\n" unless $config->{format} =~ /pileup|vcf|guess/i;
-    }
-
-    # connection settings for Ensembl Genomes
-    if($config->{genomes}) {
-        $config->{host} ||= 'mysql.ebi.ac.uk';
-        $config->{port} ||= 4157;
-    }
-
-    # connection settings for main Ensembl
-    else {
-        $config->{species} ||= "homo_sapiens";
-        $config->{host}    ||= 'ensembldb.ensembl.org';
-        $config->{port}    ||= 5306;
-    }
-
-    # output term
-    if(defined $config->{terms}) {
-        die "ERROR: Unrecognised consequence term type specified \"".$config->{terms}."\" - must be one of ensembl, so, ncbi\n" unless $config->{terms} =~ /ensembl|display|so|ncbi/i;
-        if($config->{terms} =~ /ensembl|display/i) {
-            $config->{terms} = 'display';
-        }
-        else {
-            $config->{terms} = uc($config->{terms});
-        }
-    }
-
-    # check nsSNP tools
-    foreach my $tool(grep {defined $config->{lc($_)}} qw(SIFT PolyPhen Condel)) {
-        die "ERROR: Unrecognised option for $tool \"", $config->{lc($tool)}, "\" - must be one of p (prediction), s (score) or b (both)\n" unless $config->{lc($tool)} =~ /^(s|p|b)/;
-
-        die "ERROR: $tool not available for this species\n" unless $config->{species} =~ /human|homo/i;
-
-        die "ERROR: $tool not available in standalone mode\n" if defined($config->{standalone});
-    }
-
-    # force quiet if outputting to STDOUT
-    if(defined($config->{output_file}) && $config->{output_file} =~ /stdout/i) {
-        delete $config->{verbose} if defined($config->{verbose});
-        $config->{quiet} = 1;
-    }
-
-    # summarise options if verbose
-    if(defined $config->{verbose}) {
-        my $header =<<INTRO;
-#----------------------------------#
-# ENSEMBL VARIANT EFFECT PREDICTOR #
-#----------------------------------#
-
-version $VERSION
-
-By Will McLaren (wm2\@ebi.ac.uk)
-
-Configuration options:
-
-INTRO
-        print $header;
-
-        my $max_length = (sort {$a <=> $b} map {length($_)} keys %$config)[-1];
-
-        foreach my $key(sort keys %$config) {
-            print $key.(' ' x (($max_length - length($key)) + 4)).$config->{$key}."\n";
-        }
-
-        print "\n".("-" x 20)."\n\n";
-    }
-
-    # set defaults
-    $config->{user}              ||= 'anonymous';
-    $config->{buffer_size}       ||= 5000;
-    $config->{chunk_size}        ||= '50kb';
-    $config->{output_file}       ||= "variant_effect_output.txt";
-    $config->{tmpdir}            ||= '/tmp';
-    $config->{format}            ||= 'guess';
-    $config->{terms}             ||= 'display';
-    $config->{gene}              ||= 1 unless defined($config->{whole_genome});
-    $config->{cache_region_size} ||= 1000000;
-    $config->{dir}          ||= join '/', ($ENV{'HOME'}, '.vep');
-    $config->{compress}          ||= 'zcat';
-
-    # warn users still using whole_genome flag
-    if(defined($config->{whole_genome})) {
-        debug("INFO: Whole-genome mode is now the default run-mode for the script. To disable it, use --no_whole_genome") unless defined($config->{quiet});
-    }
-
-    $config->{whole_genome}      = 1 unless defined $config->{no_whole_genome};
-    $config->{include_failed}    = 1 unless defined $config->{include_failed};
-    $config->{chunk_size}        =~ s/mb?/000000/i;
-    $config->{chunk_size}        =~ s/kb?/000/i;
-    $config->{cache_region_size} =~ s/mb?/000000/i;
-    $config->{cache_region_size} =~ s/kb?/000/i;
-
-    # cluck and display executed SQL?
-    $Bio::EnsEMBL::DBSQL::StatementHandle::cluck = 1 if defined($config->{cluck});
-
-    # standalone needs cache, can't use HGVS
-    if(defined($config->{standalone})) {
-        $config->{cache} = 1;
-
-        die("ERROR: Cannot generate HGVS coordinates in standalone mode") if defined($config->{hgvs});
-
-        die("ERROR: Cannot analyse regulatory features in standalone mode") if defined($config->{regulatory});
-    }
-
-    # no_slice_cache, prefetch and whole_genome have to be on to use cache or upfront
-    if(defined($config->{cache}) || defined($config->{upfront})) {
-        $config->{prefetch} = 1;
-        $config->{no_slice_cache} = 1;
-        $config->{whole_genome} = 1;
-        $config->{strip} = 1;
-
-        # scan should also be on for upfront
-        $config->{scan} = 1 if defined($config->{upfront});
-    }
-
-    $config->{build} = $config->{rebuild} if defined($config->{rebuild});
-
-    # force options for full build
-    if(defined($config->{build})) {
-        $config->{prefetch} = 1;
-        $config->{gene} = 1;
-        $config->{hgnc} = 1;
-        $config->{no_slice_cache} = 1;
-        $config->{cache} = 1;
-        $config->{strip} = 1;
-        $config->{write_cache} = 1;
-    }
-
-    # connect to databases
-    $config->{reg} = &connect_to_dbs($config);
-
-    # complete dir with species name and db_version
-    $config->{dir} .= '/'.(
-        join '/', (
-            defined($config->{standalone}) ? $config->{species} : ($config->{reg}->get_alias($config->{species}) || $config->{species}),
-            $config->{db_version} || $config->{reg}->software_version
-        )
-    );
-
-    # warn user cache directory doesn't exist
-    if(!-e $config->{dir}) {
-
-        # if using write_cache
-        if(defined($config->{write_cache})) {
-            debug("INFO: Cache directory ", $config->{dir}, " not found - it will be created") unless defined($config->{quiet});
-        }
-
-        # want to read cache, not found
-        elsif(defined($config->{cache})) {
-            die("ERROR: Cache directory ", $config->{dir}, " not found");
-        }
-    }
-
-    # suppress warnings that the FeatureAdpators spit if using no_slice_cache
-    Bio::EnsEMBL::Utils::Exception::verbose(1999) if defined($config->{no_slice_cache});
-
-    # get adaptors
-    if(defined($config->{cache})) {
-
-        # try and load adaptors from cache
-        if(!&load_dumped_adaptor_cache($config)) {
-            &get_adaptors($config);
-            &dump_adaptor_cache($config) if defined($config->{write_cache});
-        }
-
-        # check cached adaptors match DB params
-        else {
-            my $dbc = $config->{sa}->{dbc};
-
-            my $ok = 1;
-
-            if($dbc->{_host} ne $config->{host}) {
-
-                # ens-livemirror, useastdb and ensembldb should all have identical DBs
-                unless(
-                    (
-                        $dbc->{_host} eq 'ens-livemirror'
-                        || $dbc->{_host} eq 'ensembldb.ensembl.org'
-                        || $dbc->{_host} eq 'useastdb.ensembl.org'
-                    ) && (
-                        $config->{host} eq 'ens-livemirror'
-                        || $config->{host} eq 'ensembldb.ensembl.org'
-                        || $config->{host} eq 'useastdb.ensembl.org'
-                    )
-                ) {
-                    $ok = 0;
-                }
-
-                # but we still need to reconnect
-                debug("INFO: Defined host ", $config->{host}, " is different from cached ", $dbc->{_host}, " - reconnecting to host") unless defined($config->{quiet});
-
-                &get_adaptors($config);
-            }
-
-            if(!$ok) {
-                if(defined($config->{skip_db_check})) {
-                    debug("INFO: Defined host ", $config->{host}, " is different from cached ", $dbc->{_host}) unless defined($config->{quiet});
-                }
-                else {
-                    die "ERROR: Defined host ", $config->{host}, " is different from cached ", $dbc->{_host}, ". If you are sure this is OK, rerun with -skip_db_check flag set";
-                }
-            }
-        }
-    }
-    else {
-        &get_adaptors($config);
-        &dump_adaptor_cache($config) if defined($config->{write_cache})
-    }
-
-    # get terminal width for progress bars
-    unless(defined($config->{quiet})) {
-        my $width;
-
-        # module may not be installed
-        eval {
-            use Term::ReadKey;
-        };
-
-        if(!$@) {
-            my ($w, $h);
-
-            # module may be installed, but e.g.
-            eval {
-                ($w, $h) = GetTerminalSize();
-            };
-
-            $width = $w if defined $w;
-        }
-
-        $width ||= 60;
-        $width -= 12;
-        $config->{terminal_width} = $width;
-    }
-
-    # jump out to build cache if requested
-    if(defined($config->{build})) {
-
-        # build the cache
-        debug("Building cache for ".$config->{species}) unless defined($config->{quiet});
-        &build_full_cache($config, $config->{rebuild});
-
-        # exit script
-        debug("Finished building cache") unless defined($config->{quiet});
-        exit(0);
-    }
-
-    # warn user DB will be used for SIFT/PolyPhen/Condel
-    if(defined($config->{cache}) && (defined($config->{sift}) || defined($config->{polyphen}) || defined($config->{condel}) || defined($config->{hgvs}) || defined($config->{regulatory}))) {
-        debug("INFO: Database will be accessed for SIFT/PolyPhen/Condel, HGVS and regulatory features") unless defined($config->{quiet});
-    }
-
-    # get list of chrs if supplied
-    if(defined($config->{chr})) {
-        my %chrs;
-
-        foreach my $val(split /\,/, $config->{chr}) {
-            my @nnn = split /\-/, $val;
-
-            foreach my $chr($nnn[0]..$nnn[-1]) {
-                $chrs{$chr} = 1;
-            }
-        }
-
-        $config->{chr} = \%chrs;
-    }
-
-    # get input file handle
-    $config->{in_file_handle} = &get_in_file_handle($config);
-
-    # configure output file
-    $config->{out_file_handle} = &get_out_file_handle($config);
-
-    return $config;
-}
-
-# connects to DBs; in standalone mode this just loads registry module
-sub connect_to_dbs {
-    my $config = shift;
-
-    # get registry
-    my $reg = 'Bio::EnsEMBL::Registry';
-
-    unless(defined($config->{standalone})) {
-        # load DB options from registry file if given
-        if(defined($config->{registry})) {
-            debug("Loading DB config from registry file ", $config->{registry}) unless defined($config->{quiet});
-            $reg->load_all(
-                $config->{registry},
-                $config->{verbose},
-                undef,
-                $config->{no_slice_cache}
-            );
-        }
-
-        # otherwise manually connect to DB server
-        else {
-            $reg->load_registry_from_db(
-                -host       => $config->{host},
-                -user       => $config->{user},
-                -pass       => $config->{password},
-                -port       => $config->{port},
-                -db_version => $config->{db_version},
-                -species    => $config->{species} =~ /^[a-z]+\_[a-z]+/i ? $config->{species} : undef,
-                -verbose    => $config->{verbose},
-                -no_cache   => $config->{no_slice_cache},
-            );
-        }
-
-        eval { $reg->set_reconnect_when_lost() };
-
-        if(defined($config->{verbose})) {
-            # get a meta container adaptors to check version
-            my $core_mca = $reg->get_adaptor($config->{species}, 'core', 'metacontainer');
-            my $var_mca = $reg->get_adaptor($config->{species}, 'variation', 'metacontainer');
-
-            if($core_mca && $var_mca) {
-                debug(
-                    "Connected to core version ", $core_mca->get_schema_version, " database ",
-                    "and variation version ", $var_mca->get_schema_version, " database"
-                );
-            }
-        }
-    }
-
-    return $reg;
-}
-
-# get adaptors from DB
-sub get_adaptors {
-    my $config = shift;
-
-    die "ERROR: No registry" unless defined $config->{reg};
-
-    $config->{vfa} = $config->{reg}->get_adaptor($config->{species}, 'variation', 'variationfeature');
-    $config->{tva} = $config->{reg}->get_adaptor($config->{species}, 'variation', 'transcriptvariation');
-
-    # get fake ones for species with no var DB
-    if(!defined($config->{vfa})) {
-        $config->{vfa} = Bio::EnsEMBL::Variation::DBSQL::VariationFeatureAdaptor->new_fake($config->{species});
-    }
-    else {
-        $config->{vfa}->db->include_failed_variations($config->{include_failed}) if defined($config->{vfa}->db) && $config->{vfa}->db->can('include_failed_variations');
-    }
-
-    $config->{sa}  = $config->{reg}->get_adaptor($config->{species}, 'core', 'slice');
-    $config->{ga}  = $config->{reg}->get_adaptor($config->{species}, 'core', 'gene');
-    $config->{ta}  = $config->{reg}->get_adaptor($config->{species}, 'core', 'transcript');
-    $config->{tra}  = $config->{reg}->get_adaptor($config->{species}, 'core', 'translation');
-    $config->{mca} = $config->{reg}->get_adaptor($config->{species}, 'core', 'metacontainer');
-    $config->{csa} = $config->{reg}->get_adaptor($config->{species}, 'core', 'coordsystem');
-
-    # cache schema version
-    $config->{mca}->get_schema_version if defined $config->{mca};
-
-    # check we got slice adaptor - can't continue without a core DB
-    die("ERROR: Could not connect to core database\n") unless defined $config->{sa};
-}
-
-# gets file handle for input
-sub get_in_file_handle {
-    my $config = shift;
-
-    # define the filehandle to read input from
-    my $in_file_handle = new FileHandle;
-
-    if(defined($config->{input_file})) {
-
-        # check defined input file exists
-        die("ERROR: Could not find input file ", $config->{input_file}, "\n") unless -e $config->{input_file};
-
-        if($config->{input_file} =~ /\.gz$/){
-            $in_file_handle->open($config->{compress}." ". $config->{input_file} . " | " ) or die("ERROR: Could not read from input file ", $config->{input_file}, "\n");
-        }
-        else {
-            $in_file_handle->open( $config->{input_file} ) or die("ERROR: Could not read from input file ", $config->{in_file}, "\n");
-        }
-    }
-
-    # no file specified - try to read data off command line
-    else {
-        $in_file_handle = 'STDIN';
-        debug("Reading input from STDIN (or maybe you forgot to specify an input file?)...") unless defined $config->{quiet};
-    }
-
-    return $in_file_handle;
-}
-
-# gets file handle for output and adds header
-sub get_out_file_handle {
-    my $config = shift;
-
-    # define filehandle to write to
-    my $out_file_handle = new FileHandle;
-
-    # check if file exists
-    if(-e $config->{output_file} && !defined($config->{force_overwrite})) {
-        die("ERROR: Output file ", $config->{output_file}, " already exists. Specify a different output file with --output_file or overwrite existing file with --force_overwrite\n");
-    }
-
-    if($config->{output_file} =~ /stdout/i) {
-        $out_file_handle = *STDOUT;
-    }
-    else {
-        $out_file_handle->open(">".$config->{output_file}) or die("ERROR: Could not write to output file ", $config->{output_file}, "\n");
-    }
-
-    # make header
-    my $time = &get_time;
-    my $db_string = $config->{mca}->dbc->dbname." on ".$config->{mca}->dbc->host if defined $config->{mca};
-    $db_string .= "\n## Using cache in ".$config->{dir} if defined($config->{cache});
-    my $version_string =
-        "Using API version ".$config->{reg}->software_version.
-        ", DB version ".(defined $config->{mca} && $config->{mca}->get_schema_version ? $config->{mca}->get_schema_version : '?');
-
-    my $header =<<HEAD;
-## ENSEMBL VARIANT EFFECT PREDICTOR v$VERSION
-## Output produced at $time
-## Connected to $db_string
-## $version_string
-## Extra column keys:
-## HGNC         : HGNC gene identifier
-## ENSP         : Ensembl protein identifer
-## HGVSc        : HGVS coding sequence name
-## HGVSp        : HGVS protein sequence name
-## SIFT         : SIFT prediction
-## PolyPhen     : PolyPhen prediction
-## Condel       : Condel SIFT/PolyPhen consensus prediction
-## MATRIX       : The source and identifier of a transcription factor binding profile aligned at this position
-## HIGH_INF_POS : A flag indicating if the variant falls in a high information position of a transcription factor binding profile
-HEAD
-
-    # add headers
-    print $out_file_handle $header;
-
-    # add column headers
-    print $out_file_handle '#', (join "\t", @OUTPUT_COLS);
-    print $out_file_handle "\n";
-
-    return $out_file_handle;
-}
-
-# parses a line of input
-sub parse_line {
-    my $config = shift;
-    my $line   = shift;
-
-    my @data = (split /\s+/, $_);
-
-    # pileup: chr1 60 T A
-    if(
-       ($config->{format} =~ /pileup/i) ||
-       (
-            $data[0] =~ /(chr)?\w+/ &&
-            $data[1] =~ /\d+/ &&
-            $data[2] =~ /^[ACGTN-]+$/ &&
-            $data[3] =~ /^[ACGTNRYSWKM*+\/-]+$/
-        )
-    ) {
-        my @return = ();
-
-        if($data[2] ne "*"){
-            my $var;
-
-            if($data[3] =~ /^[A|C|G|T]$/) {
-                $var = $data[3];
-            }
-            else {
-                ($var = unambiguity_code($data[3])) =~ s/$data[2]//ig;
-            }
-            if(length($var)==1){
-                push @return, [$data[0], $data[1], $data[1], $data[2]."/".$var, 1, undef];
-            }
-            else{
-                for my $nt(split //,$var){
-                    push @return, [$data[0], $data[1], $data[1], $data[2]."/".$nt, 1, undef];
-                }
-            }
-        }
-        else{ #indel
-            my @genotype=split /\//,$data[3];
-            foreach my $allele(@genotype){
-                if(substr($allele,0,1) eq "+") { #ins
-                    push @return, [$data[0], $data[1]+1, $data[1], "-/".substr($allele,1), 1, undef];
-                }
-                elsif(substr($allele,0,1) eq "-"){ #del
-                    push @return, [$data[0], $data[1], $data[1]+length($data[3])-4, substr($allele,1)."/-", 1, undef];
-                }
-                elsif($allele ne "*"){
-                    warn("WARNING: invalid pileup indel genotype: $line\n") unless defined $config->{quiet};
-                    push @return, ['non-variant'];
-                }
-            }
-        }
-        return \@return;
-    }
-
-    # VCF: 20      14370   rs6054257 G     A      29    0       NS=58;DP=258;AF=0.786;DB;H2          GT:GQ:DP:HQ
-    elsif(
-        ($config->{format} =~ /vcf/i) ||
-        (
-            $data[0] =~ /(chr)?\w+/ &&
-            $data[1] =~ /\d+/ &&
-            $data[3] =~ /^[ACGTN-]+$/ &&
-            $data[4] =~ /^([\.ACGTN-]+\,?)+$/
-        )
-    ) {
-
-        # non-variant line in VCF, return dummy line
-        if($data[4] eq '.') {
-            return [['non-variant']];
-        }
-
-        # get relevant data
-        my ($chr, $start, $end, $ref, $alt) = ($data[0], $data[1], $data[1], $data[3], $data[4]);
-
-        if(defined $config->{gp}) {
-            $chr = undef;
-            $start = undef;
-
-            foreach my $pair(split /\;/, $data[7]) {
-                my ($key, $value) = split /\=/, $pair;
-                if($key eq 'GP') {
-                    ($chr,$start) = split /\:/, $value;
-                    $end = $start;
-                }
-            }
-
-            unless(defined($chr) and defined($start)) {
-                warn "No GP flag found in INFO column" unless defined $config->{quiet};
-                return [['non-variant']];
-            }
-        }
-
-        # adjust end coord
-        $end += (length($ref) - 1);
-
-        # find out if any of the alt alleles make this an insertion or a deletion
-        my ($is_indel, $is_sub, $ins_count, $total_count);
-        foreach my $alt_allele(split /\,/, $alt) {
-            $is_indel = 1 if $alt_allele =~ /D|I/;
-            $is_indel = 1 if length($alt_allele) != length($ref);
-            $is_sub = 1 if length($alt_allele) == length($ref);
-            $ins_count++ if length($alt_allele) > length($ref);
-            $total_count++;
-        }
-
-        # multiple alt alleles?
-        if($alt =~ /\,/) {
-            if($is_indel) {
-
-                my @alts;
-
-                if($alt =~ /D|I/) {
-                    foreach my $alt_allele(split /\,/, $alt) {
-                        # deletion (VCF <4)
-                        if($alt_allele =~ /D/) {
-                            push @alts, '-';
-                        }
-
-                        elsif($alt_allele =~ /I/) {
-                            $alt_allele =~ s/^I//g;
-                            push @alts, $alt_allele;
-                        }
-                    }
-                }
-
-                else {
-                    $ref = substr($ref, 1);
-                    $ref = '-' if $ref eq '';
-                    $start++;
-
-                    foreach my $alt_allele(split /\,/, $alt) {
-                        $alt_allele = substr($alt_allele, 1);
-                        $alt_allele = '-' if $alt_allele eq '';
-                        push @alts, $alt_allele;
-                    }
-                }
-
-                $alt = join "/", @alts;
-            }
-
-            else {
-                # for substitutions we just need to replace ',' with '/' in $alt
-                $alt =~ s/\,/\//;
-            }
-        }
-
-        else {
-            if($is_indel) {
-                # deletion (VCF <4)
-                if($alt =~ /D/) {
-                    my $num_deleted = $alt;
-                    $num_deleted =~ s/\D+//g;
-                    $end += $num_deleted - 1;
-                    $alt = "-";
-                    $ref .= ("N" x ($num_deleted - 1)) unless length($ref) > 1;
-                }
-
-                # insertion (VCF <4)
-                elsif($alt =~ /I/) {
-                    $ref = '-';
-                    $alt =~ s/^I//g;
-                    $start++;
-                }
-
-                # insertion or deletion (VCF 4+)
-                else {
-                    # chop off first base
-                    $ref = substr($ref, 1);
-                    $alt = substr($alt, 1);
-
-                    $start++;
-
-                    if($ref eq '') {
-                        # make ref '-' if no ref allele left
-                        $ref = '-';
-                    }
-
-                    # make alt '-' if no alt allele left
-                    $alt = '-' if $alt eq '';
-                }
-            }
-        }
-
-        return [[$chr, $start, $end, $ref."/".$alt, 1, ($data[2] eq '.' ? undef : $data[2])]];
-
-    }
-
-    # our format
-    else {
-        # we allow commas as delimiter so re-split
-        @data = (split /\s+|\,/, $_);
-        return [\@data];
-    }
-}
-
-# takes a hash of VFs and fetches consequences by pre-fetching overlapping transcripts
-# from database and/or cache
-sub whole_genome_fetch {
-    my $config = shift;
-    my $vf_hash = shift;
-    my $transcript_cache = shift;
-    my $include_regions = shift;
-
-    my $up_down_size = MAX_DISTANCE_FROM_TRANSCRIPT;
-
-    my (%vf_done, @finished_vfs, %seen_trs);
-
-    # convert regions to cached sizes
-    my $converted_regions = &convert_regions($config, $include_regions) if defined($config->{cache});
-
-    foreach my $chr(sort {$a <=> $b} keys %$vf_hash) {
-        if(defined($config->{standalone}) && !-e $config->{dir}.'/'.$chr) {
-            debug("No cache found for chromsome $chr") unless defined($config->{quiet});
-            next;
-        }
-
-        my $slice_cache;
-
-        debug("Analyzing chromosome $chr") unless defined($config->{quiet});
-
-        my $use_regions = defined($config->{cache}) ? $converted_regions : $include_regions;
-        my ($count_from_db, $count_from_cache, $count_duplicates) = (0, 0, 0);
-
-        if(!defined($transcript_cache->{$chr})) {
-
-            # no regions defined (this probably shouldn't happen)
-            if(!defined($use_regions->{$chr})) {
-
-                # spoof regions covering whole chromosome
-                my $start = 1;
-                my $end = $config->{cache_region_size};
-                my $slice = &get_slice($config, $chr);
-
-                if(defined($slice)) {
-                    while($start < $slice->end) {
-                        push @{$use_regions->{$chr}}, $start.'-'.$end;
-                        $start += $config->{cache_region_size};
-                        $end += $config->{cache_region_size};
-                    }
-                }
-            }
-
-            # check we have defined regions
-            if(defined($use_regions->{$chr})) {
-                my $region_count = scalar @{$use_regions->{$chr}};
-                my $counter;
-
-                debug("Reading transcript data from cache and/or database") unless defined($config->{quiet});
-
-                foreach my $region(sort {(split /\-/, $a)[0] <=> (split /\-/, $b)[1]} @{$use_regions->{$chr}}) {
-                    &progress($config, $counter++, $region_count);
-
-                    # skip regions beyond the end of the chr
-                    next if defined($slice_cache->{$chr}) && (split /\-/, $region)[0] > $slice_cache->{$chr}->length;
-
-                    # force quiet so other methods don't mess up the progress bar
-                    my $quiet = $config->{quiet};
-                    $config->{quiet} = 1;
-
-                    # try and load cache from disk if using cache
-                    my $tmp_cache;
-                    if(defined($config->{cache})) {
-                        $tmp_cache = &load_dumped_transcript_cache($config, $chr, $region);
-                        $count_from_cache += scalar @{$tmp_cache->{$chr}} if defined($tmp_cache->{$chr});
-                    }
-
-                    # no cache found on disk or not using cache
-                    if(!defined($tmp_cache->{$chr})) {
-
-                        if(defined($config->{standalone})) {
-                            debug("WARNING: Could not find cache for $chr\:$region") unless defined($config->{quiet});
-                            next;
-                        }
-
-                        # spoof temporary region hash
-                        my $tmp_hash;
-                        push @{$tmp_hash->{$chr}}, $region;
-
-                        $tmp_cache = &cache_transcripts($config, $tmp_hash);
-
-                        # make it an empty arrayref that gets cached
-                        # so we don't get confused and reload next time round
-                        $tmp_cache->{$chr} ||= [];
-
-                        $count_from_db += scalar @{$tmp_cache->{$chr}};
-
-                        # dump to disk if writing to cache
-                        &dump_transcript_cache($config, $tmp_cache, $chr, $region) if defined($config->{write_cache});
-                    }
-
-                    # add loaded transcripts to main cache
-                    if(defined($tmp_cache->{$chr})) {
-                        while(my $tr = shift @{$tmp_cache->{$chr}}) {
-
-                            # track already added transcripts by dbID
-                            my $dbID = $tr->dbID;
-                            if($seen_trs{$dbID}) {
-                                $count_duplicates++;
-                                next;
-                            }
-                            $seen_trs{$dbID} = 1;
-
-                            push @{$transcript_cache->{$chr}}, $tr;
-                        }
-                    }
-
-                    $transcript_cache->{$chr} ||= [];
-
-                    undef $tmp_cache;
-
-                    # restore quiet status
-                    $config->{quiet} = $quiet;
-
-                    # build slice cache
-                    $slice_cache = &build_slice_cache($config, $transcript_cache) unless defined($slice_cache->{$chr});
-                }
-
-                &end_progress($config);
-            }
-        }
-
-        # skip chr if no cache
-        next unless defined($transcript_cache->{$chr});
-
-        # copy slice from transcript to slice cache
-        $slice_cache = &build_slice_cache($config, $transcript_cache) unless defined($slice_cache->{$chr});
-
-        my $tr_count = scalar @{$transcript_cache->{$chr}};
-
-        debug("Retrieved $tr_count transcripts ($count_from_cache cached, $count_from_db DB, $count_duplicates duplicates)") unless defined($config->{quiet});
-        debug("Analyzing variants") unless defined($config->{quiet});
-
-        my $tr_counter;
-
-        while($tr_counter < $tr_count) {
-
-            &progress($config, $tr_counter, $tr_count);
-
-            my $tr = $transcript_cache->{$chr}->[$tr_counter++];
-
-            # do each overlapping VF
-            my $s = $tr->start - $up_down_size;
-            my $e = $tr->end + $up_down_size;
-
-            # get the chunks this transcript overlaps
-            my %chunks;
-            $chunks{$_} = 1 for (int($s/$config->{chunk_size})..int($e/$config->{chunk_size}));
-            map {delete $chunks{$_} unless defined($vf_hash->{$chr}{$_})} keys %chunks;
-
-            foreach my $chunk(keys %chunks) {
-                foreach my $pos(grep {$_ >= $s && $_ <= $e} keys %{$vf_hash->{$chr}{$chunk}}) {
-                    foreach my $vf(@{$vf_hash->{$chr}{$chunk}{$pos}}) {
-
-                        # pinch slice from slice cache if we don't already have it
-                        $_->{slice} ||= $slice_cache->{$chr} for @{$vf_hash->{$chr}{$chunk}{$pos}};
-
-                        my $tv = Bio::EnsEMBL::Variation::TranscriptVariation->new(
-                            -transcript => $tr,
-                            -variation_feature => $vf,
-                            -adaptor => $config->{tva},
-                            -no_ref_check => 1
-                        );
-
-                        # prefetching stuff here prevents doing loads at the
-                        # end and makes progress reporting more useful
-                        $tv->_prefetch_for_vep;
-
-                        $vf->add_TranscriptVariation($tv);
-                    }
-                }
-            }
-        }
-
-        # sort results into @finished_vfs array
-        foreach my $chunk(sort {$a <=> $b} keys %{$vf_hash->{$chr}}) {
-            foreach my $pos(sort {$a <=> $b} keys %{$vf_hash->{$chr}{$chunk}}) {
-
-                # pinch slice from slice cache if we don't already have it
-                $_->{slice} ||= $slice_cache->{$chr} for @{$vf_hash->{$chr}{$chunk}{$pos}};
-
-                # add to final array
-                push @finished_vfs, @{$vf_hash->{$chr}{$chunk}{$pos}};
-            }
-        }
-
-        &end_progress($config);
-
-        debug("Calculating and writing output") unless defined($config->{quiet});
-        &print_consequences($config, \@finished_vfs);
-
-        @finished_vfs = ();
-
-        # clean hash
-        delete $vf_hash->{$chr};
-
-        delete $transcript_cache->{$chr} if defined($config->{cache});
-    }
-}
-
-# gets existing VFs for a vf_hash
-sub check_existing_hash {
-    my $config = shift;
-    my $vf_hash = shift;
-    my $variation_cache;
-
-    debug("Checking for existing variations") unless defined($config->{quiet});
-
-    my ($chunk_count, $counter);
-    $chunk_count += scalar keys %{$vf_hash->{$_}} for keys %{$vf_hash};
-
-    foreach my $chr(keys %{$vf_hash}) {
-
-        my %loaded_regions;
-
-        foreach my $chunk(keys %{$vf_hash->{$chr}}) {
-            &progress($config, $counter++, $chunk_count);
-
-            # get the VFs for this chunk
-            my ($start, $end);
-
-            # work out start and end using chunk_size
-            $start = $config->{chunk_size} * $chunk;
-            $end = $config->{chunk_size} * ($chunk + 1);
-
-            # using cache?
-            if(defined($config->{cache})) {
-                my $tmp_regions;
-                push @{$tmp_regions->{$chr}}, $start.'-'.$end;
-
-                my $converted_regions = &convert_regions($config, $tmp_regions);
-
-                foreach my $region(@{$converted_regions->{$chr}}) {
-
-                    unless($loaded_regions{$region}) {
-                        my $tmp_cache = &load_dumped_variation_cache($config, $chr, $region);
-
-                        # load from DB if not found in cache
-                        if(!defined($tmp_cache->{$chr})) {
-                            if(defined($config->{standalone})) {
-                                debug("WARNING: Could not find variation cache for $chr\:$region") unless defined($config->{quiet});
-                                next;
-                            }
-
-                            $tmp_cache->{$chr} = &get_variations_in_region($config, $chr, $region);
-                            &dump_variation_cache($config, $tmp_cache, $chr, $region) if defined($config->{write_cache});
-                        }
-
-                        # merge tmp_cache with the main cache
-                        foreach my $key(keys %{$tmp_cache->{$chr}}) {
-                            $variation_cache->{$chr}->{$key} = $tmp_cache->{$chr}->{$key};
-                            delete $tmp_cache->{$chr}->{$key};
-                        }
-
-                        # clear memory
-                        undef $tmp_cache;
-
-                        # record this region as fetched
-                        $loaded_regions{$region} = 1;
-                    }
-                }
-            }
-
-            # no cache, get all variations in region from DB
-            else {
-                $variation_cache->{$chr} = &get_variations_in_region($config, $chr, $start.'-'.$end);
-            }
-
-            # now compare retrieved vars with vf_hash
-            foreach my $pos(keys %{$vf_hash->{$chr}->{$chunk}}) {
-                foreach my $var(@{$vf_hash->{$chr}->{$chunk}->{$pos}}) {
-                    my @found;
-
-                    if(defined($variation_cache->{$chr})) {
-                        if(my $existing_vars = $variation_cache->{$chr}->{$pos}) {
-                            foreach my $existing_var(@$existing_vars) {
-                                push @found, $existing_var->[0] unless &is_var_novel($config, $existing_var, $var);
-                            }
-                        }
-                    }
-
-                    $var->{existing} = join ",", @found;
-                    $var->{existing} ||= '-';
-                }
-            }
-        }
-
-        delete $variation_cache->{$chr};
-    }
-
-    &end_progress($config);
-}
-
-# gets a slice from the slice adaptor
-sub get_slice {
-    my $config = shift;
-    my $chr = shift;
-
-    return undef unless defined($config->{sa}) && defined($chr);
-
-    my $slice;
-
-    # first try to get a chromosome
-    eval { $slice = $config->{sa}->fetch_by_region('chromosome', $chr); };
-
-    # if failed, try to get any seq region
-    if(!defined($slice)) {
-        $slice = $config->{sa}->fetch_by_region(undef, $chr);
-    }
-
-    return $slice;
-}
-
-
-
-
-# METHODS THAT DEAL WITH "REGIONS"
-##################################
-
-# scans file to get all slice bits we need
-sub scan_file() {
-    my $config = shift;
-
-    my $in_file_handle = $config->{in_file_handle};
-
-    my %include_regions;
-
-    debug("Scanning input file") unless defined($config->{quiet});
-
-    while(<$in_file_handle>) {
-        chomp;
-
-        # header line?
-        next if /^\#/;
-
-        # some lines (pileup) may actually parse out into more than one variant)
-        foreach my $sub_line(@{&parse_line($config, $_)}) {
-
-            # get the sub-line into named variables
-            my ($chr, $start, $end, $allele_string, $strand, $var_name) = @{$sub_line};
-            $chr =~ s/chr//ig unless $chr =~ /^chromosome$/i;
-            $chr = 'MT' if $chr eq 'M';
-
-            next if defined($config->{chr}) && !$config->{chr}->{$chr};
-
-            $include_regions{$chr} ||= [];
-
-            &add_region($start, $end, $include_regions{$chr});
-        }
-    }
-
-    # close filehandle and recycle
-    close $in_file_handle;
-    $config->{in_file_handle} = &get_in_file_handle($config);
-
-    # merge regions
-    &merge_regions(\%include_regions);
-
-    return \%include_regions;
-}
-
-# gets regions from VF hash
-sub regions_from_hash {
-    my $config = shift;
-    my $vf_hash = shift;
-
-    my %include_regions;
-
-    # if using cache we just want the regions of cache_region_size
-    # since that's what we'll get from the cache (or DB if no cache found)
-    if(defined($config->{cache})) {
-
-        my $region_size = $config->{cache_region_size};
-
-        foreach my $chr(keys %$vf_hash) {
-            $include_regions{$chr} = [];
-            my %temp_regions;
-
-            foreach my $chunk(keys %{$vf_hash->{$chr}}) {
-                foreach my $pos(keys %{$vf_hash->{$chr}{$chunk}}) {
-                    my ($s, $e) = ($pos - MAX_DISTANCE_FROM_TRANSCRIPT, $pos + MAX_DISTANCE_FROM_TRANSCRIPT);
-
-                    my $low = int ($s / $region_size);
-                    my $high = int ($e / $region_size) + 1;
-
-                    for my $i($low..($high - 1)) {
-                        $temp_regions{(($i * $region_size) + 1).'-'.(($i + 1) * $region_size)} = 1;
-                    }
-                }
-            }
-
-            @{$include_regions{$chr}} = keys %temp_regions;
-        }
-    }
-
-    # if no cache we don't want to fetch more than is necessary, so find the
-    # minimum covered region of the variations in the hash
-    else {
-        foreach my $chr(keys %$vf_hash) {
-            $include_regions{$chr} = [];
-
-            foreach my $chunk(keys %{$vf_hash->{$chr}}) {
-                foreach my $pos(keys %{$vf_hash->{$chr}{$chunk}}) {
-                    &add_region($_->start, $_->end, $include_regions{$chr}) for @{$vf_hash->{$chr}{$chunk}{$pos}};
-                }
-            }
-        }
-
-        # merge regions
-        &merge_regions(\%include_regions);
-    }
-
-    return \%include_regions;
-}
-
-# adds a region to region list, expanding existing one if overlaps
-sub add_region {
-    my $start = shift;
-    my $end = shift;
-    my $region_list = shift;
-
-    # fix end for insertions
-    $end = $start if $end < $start;
-
-    my $added = 0;
-    my $i = 0;
-
-    while ($i < scalar @$region_list) {
-        my ($region_start, $region_end) = split /\-/, $region_list->[$i];
-
-        if($start <= $region_end && $end >= $region_start) {
-            my $new_region_start = ($start < $end ? $start : $end) - MAX_DISTANCE_FROM_TRANSCRIPT;
-            my $new_region_end = ($start > $end ? $start : $end) + MAX_DISTANCE_FROM_TRANSCRIPT;
-
-            $region_start = $new_region_start if $new_region_start < $region_start;
-            $region_end = $new_region_end if $new_region_end > $region_end;
-
-            $region_list->[$i] = $region_start.'-'.$region_end;
-            $added = 1;
-        }
-
-        $i++;
-    }
-
-    unless($added) {
-        push @{$region_list}, ($start - MAX_DISTANCE_FROM_TRANSCRIPT).'-'.($end + MAX_DISTANCE_FROM_TRANSCRIPT);
-    }
-}
-
-# merges overlapping regions from scans
-sub merge_regions {
-    my $include_regions = shift;
-
-    # now merge overlapping regions
-    foreach my $chr(keys %$include_regions) {
-        my $max_index = $#{$include_regions->{$chr}};
-        my (@new_regions, %skip);
-
-        for my $i(0..$max_index) {
-            next if $skip{$i};
-            my ($s, $e) = split /\-/, $include_regions->{$chr}[$i];
-
-            for my $j(($i+1)..$max_index) {
-                next if $skip{$j};
-                my ($ns, $ne) = split /\-/, $include_regions->{$chr}[$j];
-
-                if($s <= $ne && $e >= $ns) {
-                    $s = $ns if $ns < $s;
-                    $e = $ne if $ne > $e;
-
-                    $skip{$j} = 1;
-                }
-            }
-
-            push @new_regions, $s.'-'.$e;
-        }
-
-        # replace original
-        $include_regions->{$chr} = \@new_regions;
-
-        $config->{region_count} += scalar @new_regions;
-    }
-
-    return $include_regions;
-}
-
-# converts regions as determined by scan_file to regions loadable from cache
-sub convert_regions {
-    my $config = shift;
-    my $regions = shift;
-
-    return undef unless defined $regions;
-
-    my $region_size = $config->{cache_region_size};
-
-    my %new_regions;
-
-    foreach my $chr(keys %$regions) {
-        my %temp_regions;
-
-        foreach my $region(@{$regions->{$chr}}) {
-            my ($s, $e) = split /\-/, $region;
-
-            my $low = int ($s / $region_size);
-            my $high = int ($e / $region_size) + 1;
-
-            for my $i($low..($high - 1)) {
-                $temp_regions{(($i * $region_size) + 1).'-'.(($i + 1) * $region_size)} = 1;
-            }
-        }
-
-        @{$new_regions{$chr}} = keys %temp_regions;
-    }
-
-    return \%new_regions;
-}
-
-
-
-
-
-# CACHE METHODS
-###############
-
-# get transcripts for slices
-sub cache_transcripts {
-    my $config = shift;
-    my $include_regions = shift;
-
-    my $transcript_cache;
-    my $i;
-
-    debug("Caching transcripts") unless defined($config->{quiet});
-
-    foreach my $chr(keys %$include_regions) {
-
-        my $slice = &get_slice($config, $chr);
-
-        next unless defined $slice;
-
-        # prefetch some things
-        $slice->is_circular;
-
-        # trim bumf off the slice
-        delete $slice->{coord_system}->{adaptor} if defined($config->{write_cache});
-
-        # no regions?
-        if(!scalar @{$include_regions->{$chr}}) {
-            my $start = 1;
-            my $end = $config->{cache_region_size};
-
-            while($start < $slice->end) {
-                push @{$include_regions->{$chr}}, $start.'-'.$end;
-                $start += $config->{cache_region_size};
-                $end += $config->{cache_region_size};
-            }
-        }
-
-        my $region_count;
-
-        if(scalar keys %$include_regions == 1) {
-            my ($chr) = keys %$include_regions;
-            $region_count = scalar @{$include_regions->{$chr}};
-            debug("Caching transcripts for chromosome $chr") unless defined($config->{quiet});
-        }
-
-        foreach my $region(@{$include_regions->{$chr}}) {
-            &progress($config, $i++, $region_count || $config->{region_count});
-
-            my ($s, $e) = split /\-/, $region;
-
-            # sanity check start and end
-            $s = 1 if $s < 1;
-            $e = $slice->end if $e > $slice->end;
-
-            # get sub-slice
-            my $sub_slice = $slice->sub_Slice($s, $e);
-
-            # add transcripts to the cache, via a transfer to the chrom's slice
-            if(defined($sub_slice)) {
-                foreach my $gene(@{$sub_slice->get_all_Genes(undef, undef, 1)}) {
-                    my $gene_stable_id = $gene->stable_id;
-
-                    foreach my $tr(map {$_->transfer($slice)} @{$gene->get_all_Transcripts}) {
-                        $tr->{_gene_stable_id} = $gene_stable_id;
-
-                        if(defined($config->{prefetch})) {
-                            $tr->{_gene} = $gene;
-                            &prefetch_transcript_data($config, $tr);
-                            delete $tr->{_gene};
-                        }
-
-                        # strip some unnecessary data from the transcript object
-                        &clean_transcript($tr) if defined($config->{write_cache});
-
-                        push @{$transcript_cache->{$chr}}, $tr;
-                    }
-                }
-            }
-        }
-    }
-
-    &end_progress($config);
-
-    return $transcript_cache;
-}
-
-# gets rid of extra bits of info attached to the transcript that we don't need
-sub clean_transcript {
-    my $tr = shift;
-
-    foreach my $key(qw(display_xref external_db external_display_name external_name external_status created_date status description edits_enabled modified_date)) {
-        delete $tr->{$key} if defined($tr->{$key});
-    }
-
-    # clean all attributes but miRNA
-    if(defined($tr->{attributes})) {
-        my @new_atts;
-        foreach my $att(@{$tr->{attributes}}) {
-            push @new_atts, $att if $att->{code} eq 'miRNA';
-        }
-        $tr->{attributes} = \@new_atts;
-    }
-
-    $tr->{analysis} = {};
-
-    # sometimes the translation's transcript points to another ref
-    $tr->{translation}->{transcript} = $tr if defined $tr->{translation};
-}
-
-# build slice cache from transcript cache
-sub build_slice_cache {
-    my $config = shift;
-    my $transcript_cache = shift;
-
-    my %slice_cache;
-
-    foreach my $chr(keys %$transcript_cache) {
-
-        $slice_cache{$chr} = scalar @{$transcript_cache->{$chr}} ? $transcript_cache->{$chr}[0]->slice : &get_slice($config, $chr);
-
-        # reattach adaptor to the coord system
-        $slice_cache{$chr}->{coord_system}->{adaptor} ||= $config->{csa};
-    }
-
-    return \%slice_cache;
-}
-
-# pre-fetches per-transcript data
-sub prefetch_transcript_data {
-    my $config = shift;
-    my $tran = shift;
-
-    # introns, translateable_seq, mapper
-    $tran->{_variation_effect_feature_cache}->{introns} ||= $tran->get_all_Introns;
-    $tran->{_variation_effect_feature_cache}->{translateable_seq} ||= $tran->translateable_seq;
-    $tran->{_variation_effect_feature_cache}->{mapper} ||= $tran->get_TranscriptMapper;
-
-    # peptide
-    unless ($tran->{_variation_effect_feature_cache}->{peptide}) {
-        my $translation = $tran->translate;
-        $tran->{_variation_effect_feature_cache}->{peptide} = $translation ? $translation->seq : undef;
-    }
-
-    # codon table
-    unless ($tran->{_variation_effect_feature_cache}->{codon_table}) {
-        # for mithocondrial dna we need to to use a different codon table
-        my $attrib = $tran->slice->get_all_Attributes('codon_table')->[0];
-
-        $tran->{_variation_effect_feature_cache}->{codon_table} = $attrib ? $attrib->value : 1;
-    }
-
-    # gene HGNC
-    if(defined $config->{hgnc}) {
-        # get from gene cache if found already
-        if(defined($tran->{_gene}->{_hgnc})) {
-            $tran->{_gene_hgnc} = $tran->{_gene}->{_hgnc};
-        }
-        else {
-            my @entries = grep {$_->database eq 'HGNC'} @{$tran->{_gene}->get_all_DBEntries()};
-            if(scalar @entries) {
-                $tran->{_gene_hgnc} = $entries[0]->display_id;
-            }
-
-            $tran->{_gene_hgnc} ||= '-';
-
-            # cache it on the gene object too
-            $tran->{_gene}->{_hgnc} = $tran->{_gene_hgnc};
-        }
-    }
-
-    return $tran;
-}
-
-# dumps out transcript cache to file
-sub dump_transcript_cache {
-    my $config = shift;
-    my $transcript_cache = shift;
-    my $chr = shift;
-    my $region = shift;
-
-    debug("Dumping cached transcript data") unless defined($config->{quiet});
-
-    # clean the slice adaptor before storing
-    &clean_slice_adaptor($config);
-
-    &strip_transcript_cache($config, $transcript_cache);
-
-    $config->{reg}->disconnect_all;
-
-    my $dir = $config->{dir}.'/'.$chr;
-    my $dump_file = $dir.'/'.($region || "dump").'.gz';
-
-    # make directory if it doesn't exist
-    if(!(-e $dir)) {
-        system("mkdir -p ".$dir);
-    }
-
-    debug("Writing to $dump_file") unless defined($config->{quiet});
-
-    # storable
-    open my $fh, "| gzip -c > ".$dump_file or die "ERROR: Could not write to dump file $dump_file";
-    nstore_fd($transcript_cache, $fh);
-    close $fh;
-}
-
-# loads in dumped transcript cache to memory
-sub load_dumped_transcript_cache {
-    my $config = shift;
-    my $chr = shift;
-    my $region = shift;
-
-    my $dir = $config->{dir}.'/'.$chr;
-    my $dump_file = $dir.'/'.($region || "dump").'.gz';
-
-    return undef unless -e $dump_file;
-
-    debug("Reading cached transcript data for chromosome $chr".(defined $region ? "\:$region" : "")." from dumped file") unless defined($config->{quiet});
-
-    open my $fh, $config->{compress}." ".$dump_file." |" or return undef;
-    my $transcript_cache = fd_retrieve($fh);
-    close $fh;
-
-    # reattach adaptors
-    foreach my $t(@{$transcript_cache->{$chr}}) {
-        if(defined($t->{translation})) {
-            $t->{translation}->{adaptor} = $config->{tra} if defined $t->{translation}->{adaptor};
-            $t->{translation}->{transcript} = $t;
-        }
-
-        $t->{slice}->{adaptor} = $config->{sa};
-    }
-
-    return $transcript_cache;
-}
-
-# strips cache
-sub strip_transcript_cache {
-    my $config = shift;
-    my $cache = shift;
-
-    foreach my $chr(keys %$cache) {
-        foreach my $tr(@{$cache->{$chr}}) {
-            foreach my $exon(@{$tr->{_trans_exon_array}}) {
-                delete $exon->{adaptor};
-                delete $exon->{slice}->{adaptor};
-            }
-
-            delete $tr->{adaptor};
-            delete $tr->{slice}->{adaptor};
-        }
-    }
-}
-
-# cleans slice adaptor before storing in cache
-sub clean_slice_adaptor{
-    my $config = shift;
-
-    # clean some stuff off the slice adaptor
-    $config->{sa}->{asm_exc_cache} = {};
-    $config->{sa}->{sr_name_cache} = {};
-    $config->{sa}->{sr_id_cache} = {};
-    delete $config->{sa}->{db}->{seq_region_cache};
-    delete $config->{sa}->{db}->{name_cache};
-}
-
-
-# dump adaptors to cache
-sub dump_adaptor_cache {
-    my $config = shift;
-
-    $config->{reg}->disconnect_all;
-
-    my $dir = $config->{dir};
-    my $dump_file = $dir.'/adaptors.gz';
-
-    # make directory if it doesn't exist
-    if(!(-e $dir)) {
-        system("mkdir -p ".$dir);
-	}
-
-    open my $fh, "| gzip -c > ".$dump_file or die "ERROR: Could not write to dump file $dump_file";
-    nstore_fd($config, $fh);
-    close $fh;
-}
-
-# load dumped adaptors
-sub load_dumped_adaptor_cache {
-    my $config = shift;
-
-    my $dir = $config->{dir};
-    my $dump_file = $dir.'/adaptors.gz';
-
-    return undef unless -e $dump_file;
-
-    debug("Reading cached adaptor data") unless defined($config->{quiet});
-
-    open my $fh, $config->{compress}." ".$dump_file." |" or return undef;
-    my $cached_config = fd_retrieve($fh);
-    close $fh;
-
-    $config->{$_} = $cached_config->{$_} for qw(sa ga ta vfa tva mca csa);
-
-    return 1;
-}
-
-# dumps cached variations to disk
-sub dump_variation_cache {
-    my $config = shift;
-    my $v_cache = shift;
-    my $chr = shift;
-    my $region = shift;
-
-    my $dir = $config->{dir}.'/'.$chr;
-    my $dump_file = $dir.'/'.($region || "dump").'_var.gz';
-
-    # make directory if it doesn't exist
-    if(!(-e $dir)) {
-        system("mkdir -p ".$dir);
-    }
-
-    open DUMP, "| gzip -c > ".$dump_file or die "ERROR: Could not write to adaptor dump file $dump_file";
-
-    foreach my $pos(keys %{$v_cache->{$chr}}) {
-        foreach my $v(@{$v_cache->{$chr}->{$pos}}) {
-            my ($name, $source, $start, $end, $as, $strand) = @$v;
-
-            print DUMP join " ", (
-                $name,
-                $source == 1 ? '' : $source,
-                $start,
-                $end == $start ? '' : $end,
-                $as,
-                $strand == 1 ? '' : $strand,
-            );
-            print DUMP "\n";
-        }
-    }
-
-    close DUMP;
-}
-
-# loads dumped variation cache
-sub load_dumped_variation_cache {
-    my $config = shift;
-    my $chr = shift;
-    my $region = shift;
-
-    my $dir = $config->{dir}.'/'.$chr;
-    my $dump_file = $dir.'/'.($region || "dump").'_var.gz';
-
-    return undef unless -e $dump_file;
-
-    open DUMP, $config->{compress}." ".$dump_file." |" or return undef;
-
-    my $v_cache;
-
-    while(<DUMP>) {
-        chomp;
-        my ($name, $source, $start, $end, $as, $strand) = split / /, $_;
-        $source ||= 1;
-        $end ||= $start;
-        $strand ||= 1;
-
-        my @v = ($name, $source, $start, $end, $as, $strand);
-        push @{$v_cache->{$chr}->{$start}}, \@v;
-    }
-
-    close DUMP;
-
-    return $v_cache;
-}
-
-# builds a full cache for this species
-sub build_full_cache {
-    my $config = shift;
-    my $rebuild = shift;
-
-    my @slices;
-
-    if($config->{build} =~ /all/i) {
-        @slices = @{$config->{sa}->fetch_all('toplevel')};
-    }
-    else {
-        foreach my $val(split /\,/, $config->{build}) {
-            my @nnn = split /\-/, $val;
-
-            foreach my $chr($nnn[0]..$nnn[-1]) {
-                my $slice = &get_slice($config, $chr);
-                push @slices, $slice if defined($slice);
-            }
-        }
-    }
-
-    foreach my $slice(@slices) {
-        my $chr = $slice->seq_region_name;
-
-        my $regions;
-
-        # for progress
-        my $region_count = int($slice->end / $config->{cache_region_size}) + 1;
-        my $counter = 0;
-
-        # initial region
-        my ($start, $end) = (1, $config->{cache_region_size});
-
-        debug((defined($config->{rebuild}) ? "Rebuild" : "Creat")."ing cache for chromosome $chr") unless defined($config->{quiet});
-
-        while($start < $slice->end) {
-
-            &progress($config, $counter++, $region_count);
-
-            # store quiet status
-            my $quiet = $config->{quiet};
-            $config->{quiet} = 1;
-
-            # store transcripts
-            $regions->{$chr} = [$start.'-'.$end];
-            my $tmp_cache = ($rebuild ? &load_dumped_transcript_cache($config, $chr, $start.'-'.$end) : &cache_transcripts($config, $regions));
-            $tmp_cache->{$chr} ||= [];
-
-            &dump_transcript_cache($config, $tmp_cache, $chr, $start.'-'.$end);
-            undef $tmp_cache;
-
-            # store variations
-            my $variation_cache;
-            $variation_cache->{$chr} = &get_variations_in_region($config, $chr, $start.'-'.$end);
-            $variation_cache->{$chr} ||= {};
-
-            &dump_variation_cache($config, $variation_cache, $chr, $start.'-'.$end);
-            undef $variation_cache;
-
-            # restore quiet status
-            $config->{quiet} = $quiet;
-
-            # increment by cache_region_size to get next region
-            $start += $config->{cache_region_size};
-            $end += $config->{cache_region_size};
-        }
-
-        &end_progress($config);
-
-        undef $regions;
-    }
-}
-
-# format coords for printing
-sub format_coords {
-    my ($start, $end) = @_;
-
-    if(!defined($start)) {
-        return '-';
-    }
-    elsif(!defined($end)) {
-        return $start;
-    }
-    elsif($start == $end) {
-        return $start;
-    }
-    elsif($start > $end) {
-        return $end.'-'.$start;
-    }
-    else {
-        return $start.'-'.$end;
-    }
-}
-
-
-
-
-# METHODS TO FIND CO-LOCATED / EXISTING VARIATIONS
-##################################################
-
-# finds an existing VF in the db
-sub find_existing {
-    my $config = shift;
-    my $new_vf = shift;
-
-    if(defined($new_vf->adaptor->db)) {
-
-        my $sth = $new_vf->adaptor->db->dbc->prepare(qq{
-            SELECT variation_name, source_id, seq_region_start, seq_region_end, allele_string, seq_region_strand
-            FROM variation_feature
-            WHERE seq_region_id = ?
-            AND seq_region_start = ?
-            AND seq_region_end = ?
-            ORDER BY source_id ASC
-        });
-
-        $sth->execute($new_vf->slice->get_seq_region_id, $new_vf->start, $new_vf->end);
-
-        my @v;
-        for my $i(0..5) {
-            $v[$i] = undef;
-        }
-
-        $sth->bind_columns(\$v[0], \$v[1], \$v[2], \$v[3], \$v[4], \$v[5]);
-
-        my @found;
-
-        while($sth->fetch) {
-            push @found, $v[0] unless &is_var_novel($config, \@v, $new_vf);
-        }
-
-        $sth->finish();
-
-        return (scalar @found ? join ",", @found : undef);
-    }
-
-    return undef;
-}
-
-# compare a new vf to one from the cache / DB
-sub is_var_novel {
-    my $config = shift;
-    my $existing_var = shift;
-    my $new_var = shift;
-
-    my $is_novel = 1;
-
-    $is_novel = 0 if $existing_var->[2] == $new_var->start && $existing_var->[3] == $new_var->end;
-
-    if(defined($config->{check_alleles})) {
-        my %existing_alleles;
-
-        $existing_alleles{$_} = 1 for split /\//, $existing_var->[4];
-
-        my $seen_new = 0;
-        foreach my $a(split /\//, $new_var->allele_string) {
-            reverse_comp(\$a) if $new_var->strand ne $existing_var->[5];
-            $seen_new = 1 unless defined $existing_alleles{$a};
-        }
-
-        $is_novel = 1 if $seen_new;
-    }
-
-    return $is_novel;
-}
-
-# gets all variations in a region
-sub get_variations_in_region {
-    my $config = shift;
-    my $chr = shift;
-    my $region = shift;
-
-    my ($start, $end) = split /\-/, $region;
-
-    my %variations;
-
-    if(defined($config->{vfa}->db)) {
-        my $sth = $config->{vfa}->db->dbc->prepare(qq{
-            SELECT vf.variation_name, vf.source_id, vf.seq_region_start, vf.seq_region_end, vf.allele_string, vf.seq_region_strand
-            FROM variation_feature vf, seq_region s
-            WHERE s.seq_region_id = vf.seq_region_id
-            AND s.name = ?
-            AND vf.seq_region_start >= ?
-            AND vf.seq_region_start <= ?
-        });
-
-        $sth->execute($chr, $start, $end);
-
-        my @v;
-        for my $i(0..5) {
-            $v[$i] = undef;
-        }
-
-        $sth->bind_columns(\$v[0], \$v[1], \$v[2], \$v[3], \$v[4], \$v[5]);
-
-        while($sth->fetch) {
-            my @v_copy = @v;
-            push @{$variations{$v[2]}}, \@v_copy;
-        }
-
-        $sth->finish();
-    }
-
-    return \%variations;
-}
-
-
-
-
-# DEBUG AND STATUS METHODS
-##########################
-
-# gets time
-sub get_time() {
-    my @time = localtime(time());
-
-    # increment the month (Jan = 0)
-    $time[4]++;
-
-    # add leading zeroes as required
-    for my $i(0..4) {
-        $time[$i] = "0".$time[$i] if $time[$i] < 10;
-    }
-
-    # put the components together in a string
-    my $time =
-         ($time[5] + 1900)."-".
-         $time[4]."-".
-         $time[3]." ".
-        $time[2].":".
-        $time[1].":".
-        $time[0];
-
-    return $time;
-}
-
-# prints debug output with time
-sub debug {
-    my $text = (@_ ? (join "", @_) : "No message");
-    my $time = get_time;
-
-    print $time." - ".$text.($text =~ /\n$/ ? "" : "\n");
-}
-
-# update or initiate progress bar
-sub progress {
-    my ($config, $i, $total) = @_;
-
-    return if defined($config->{quiet}) || defined($config->{no_progress});
-
-    my $width = $config->{terminal_width};
-    my $percent = int(($i/$total) * 100);
-    my $numblobs = (($i/$total) * $width) - 2;
-
-    # this ensures we're not writing to the terminal too much
-    return if(defined($config->{prev_prog})) && $numblobs.'-'.$percent eq $config->{prev_prog};
-    $config->{prev_prog} = $numblobs.'-'.$percent;
-
-    printf("\r% -${width}s% 1s% 10s", '['.('=' x $numblobs).($numblobs == $width - 2 ? '=' : '>'), ']', "[ " . $percent . "% ]");
-}
-
-# end progress bar
-sub end_progress {
-    my $config = shift;
-    return if defined($config->{quiet}) || defined($config->{no_progress});
-    &progress($config, 1,1);
-    print "\n";
-    delete $config->{prev_prog};
-}
-
-# outputs usage message
-sub usage {
-    my $usage =<<END;
-#----------------------------------#
-# ENSEMBL VARIANT EFFECT PREDICTOR #
-#----------------------------------#
-
-version $VERSION
-
-By Will McLaren (wm2\@ebi.ac.uk)
-
-http://www.ensembl.org/info/docs/variation/vep/vep_script.html
-
-Usage:
-perl variant_effect_predictor.pl [arguments]
-
-Options
-=======
-
---help                 Display this message and quit
---verbose              Display verbose output as the script runs [default: off]
---quiet                Suppress status and warning messages [default: off]
---no_progress          Suppress progress bars [default: off]
-
---config               Load configuration from file. Any command line options
-                       specified overwrite those in the file [default: off]
-
--i | --input_file      Input file - if not specified, reads from STDIN. Files
-                       may be gzip compressed.
---format               Alternative input file format - one of "pileup", "vcf"
--o | --output_file     Output file. Write to STDOUT by specifying -o STDOUT - this
-                       will force --quiet [default: "variant_effect_output.txt"]
---force_overwrite      Force overwriting of output file [default: quit if file
-                       exists]
-
--t | --terms           Type of consequence terms to output - one of "ensembl", "SO",
-                       "NCBI" [default: ensembl]
-
---sift=[p|s|b]         Add SIFT [p]rediction, [s]core or [b]oth [default: off]
---polyphen=[p|s|b]     Add PolyPhen [p]rediction, [s]core or [b]oth [default: off]
---condel=[p|s|b]       Add Condel SIFT/PolyPhen consensus [p]rediction, [s]core or
-                       [b]oth [default: off]
-
-NB: SIFT, PolyPhen and Condel predictions are currently available for human only
-
---regulatory           Look for overlaps with regulatory regions. The script can
-                       also call if a variant falls in a high information position
-                       within a transcription factor binding site. Output lines have
-                       a Feature type of RegulatoryFeature or MotifFeature. Requires
-                       database connection. [default: off]
-
-NB: Regulatory consequences are currently available for human and mouse only
-
---hgnc                 If specified, HGNC gene identifiers are output alongside the
-                       Ensembl Gene identifier [default: off]
---hgvs                 Output HGVS identifiers (coding and protein). Requires database
-                       connection [default: off]
---protein              Output Ensembl protein identifer [default: off]
---gene                 Force output of Ensembl gene identifer - disabled by default
-                       unless using --cache or --no_whole_genome [default: off]
-
---coding_only          Only return consequences that fall in the coding region of
-                       transcripts [default: off]
---most_severe          Ouptut only the most severe consequence per variation.
-                       Transcript-specific columns will be left blank. [default: off]
---summary              Ouptut only a comma-separated list of all consequences per
-                       variation. Transcript-specific columns will be left blank.
-                       [default: off]
-
---check_ref            If specified, checks supplied reference allele against stored
-                       entry in Ensembl Core database [default: off]
---check_existing       If specified, checks for existing co-located variations in the
-                       Ensembl Variation database [default: off]
---check_alleles        If specified, the alleles of existing co-located variations
-                       are compared to the input; an existing variation will only
-                       be reported if no novel allele is in the input (strand is
-                       accounted for) [default: off]
-
---chr [list]           Select a subset of chromosomes to analyse from your file. Any
-                       data not on this chromosome in the input will be skipped. The
-                       list can be comma separated, with "-" characters representing
-                       an interval [default: off]
---gp                   If specified, tries to read GRCh37 position from GP field in the
-                       INFO column of a VCF file. Only applies when VCF is the input
-                       format and human is the species [default: off]
-
---species              Species to use [default: "human"]
---host                 Manually define database host [default: "ensembldb.ensembl.org"]
--u | --user            Database username [default: "anonymous"]
---port                 Database port [default: 5306]
---password             Database password [default: no password]
---genomes              Sets DB connection params for Ensembl Genomes [default: off]
---registry             Registry file to use defines DB connections [default: off]
-                       Defining a registry file overrides above connection settings.
---db_version=[number]  Force script to load DBs from a specific Ensembl version. Not
-                       advised due to likely incompatibilities between API and DB
-
---no_whole_genome      Run in old-style, non-whole genome mode [default: off]
---buffer_size          Sets the number of variants sent in each batch [default: 5000]
-                       Increasing buffer size can retrieve results more quickly
-                       but requires more memory. Only applies to whole genome mode.
-
---cache                Enables read-only use of cache [default: off]
---dir [directory]      Specify the base cache directory to use [default: "\$HOME/.vep/"]
---write_cache          Enable writing to cache [default: off]
---build [all|list]     Build a complete cache for the selected species. Build for all
-                       chromosomes with --build all, or a list of chromosomes (see
-                       --chr). DO NOT USE WHEN CONNECTED TO PUBLIC DB SERVERS AS THIS
-                       VIOLATES OUR FAIR USAGE POLICY [default: off]
-
---compress             Specify utility to decompress cache files - may be "gzcat" or
-                       "gzip -dc Only use if default does not work [default: zcat]
-
---skip_db_check        ADVANCED! Force the script to use a cache built from a different
-                       database than specified with --host. Only use this if you are
-                       sure the hosts are compatible (e.g. ensembldb.ensembl.org and
-                       useastdb.ensembl.org) [default: off]
---cache_region_size    ADVANCED! The size in base-pairs of the region covered by one
-                       file in the cache. [default: 1MB]
-END
-
-    print $usage;
-}
--- a/variant_effect_predictor/.#variant_effect_predictor.pl.1.19	Fri Aug 03 10:04:48 2012 -0400
+++ /dev/null	Thu Jan 01 00:00:00 1970 +0000
@@ -1,1511 +0,0 @@
-#!/usr/bin/perl
-
-=head1 LICENSE
-
-  Copyright (c) 1999-2012 The European Bioinformatics Institute and
-  Genome Research Limited.  All rights reserved.
-
-  This software is distributed under a modified Apache license.
-  For license details, please see
-
-    http://www.ensembl.org/info/about/code_licence.html
-
-=head1 CONTACT
-
-  Please email comments or questions to the public Ensembl
-  developers list at <dev@ensembl.org>.
-
-  Questions may also be sent to the Ensembl help desk at
-  <helpdesk@ensembl.org>.
-
-=cut
-
-=head1 NAME
-
-Variant Effect Predictor - a script to predict the consequences of genomic variants
-
-http://www.ensembl.org/info/docs/variation/vep/vep_script.html
-
-Version 2.2
-
-by Will McLaren (wm2@ebi.ac.uk)
-=cut
-
-use strict;
-use Getopt::Long;
-use FileHandle;
-use FindBin qw($Bin);
-use lib $Bin;
-
-use Bio::EnsEMBL::Variation::Utils::Sequence qw(unambiguity_code);
-use Bio::EnsEMBL::Variation::Utils::VEP qw(
-    parse_line
-    vf_to_consequences
-    validate_vf
-    convert_to_vcf
-    load_dumped_adaptor_cache
-    dump_adaptor_cache
-    get_all_consequences
-    get_slice
-    build_full_cache
-    read_cache_info
-    get_time
-    debug
-    @OUTPUT_COLS
-    @REG_FEAT_TYPES
-    %FILTER_SHORTCUTS
-);
-
-# global vars
-my $VERSION = '2.3';
-
-# set output autoflush for progress bars
-$| = 1;
-
-# configure from command line opts
-my $config = &configure(scalar @ARGV);
-
-# run the main sub routine
-&main($config);
-
-# this is the main sub-routine - it needs the configured $config hash
-sub main {
-    my $config = shift;
-
-    debug("Starting...") unless defined $config->{quiet};
-
-    my $tr_cache = {};
-    my $rf_cache = {};
-
-    # create a hash to hold slices so we don't get the same one twice
-    my %slice_cache = ();
-
-    my @vfs;
-    my ($vf_count, $total_vf_count);
-    my $in_file_handle = $config->{in_file_handle};
-
-    # initialize line number in config
-    $config->{line_number} = 0;
-
-    # read the file
-    while(<$in_file_handle>) {
-        chomp;
-
-        $config->{line_number}++;
-
-        # header line?
-        if(/^\#/) {
-            if(defined($config->{vcf})) {
-                push @{$config->{headers}}, $_;
-            }
-            next;
-        }
-
-        # configure output file
-        $config->{out_file_handle} ||= &get_out_file_handle($config);
-
-        # some lines (pileup) may actually parse out into more than one variant
-        foreach my $vf(@{&parse_line($config, $_)}) {
-
-            $vf->{_line} = $_ ;#if defined($config->{vcf}) || defined($config->{original});
-
-            # now get the slice
-            if(!defined($vf->{slice})) {
-                my $slice;
-
-                # don't get slices if we're using cache
-                # we can steal them from transcript objects later
-                if((!defined($config->{cache}) && !defined($config->{whole_genome})) || defined($config->{check_ref}) || defined($config->{convert})) {
-
-                    # check if we have fetched this slice already
-                    if(defined $slice_cache{$vf->{chr}}) {
-                        $slice = $slice_cache{$vf->{chr}};
-                    }
-
-                    # if not create a new one
-                    else {
-
-                        $slice = &get_slice($config, $vf->{chr});
-
-                        # if failed, warn and skip this line
-                        if(!defined($slice)) {
-                            warn("WARNING: Could not fetch slice named ".$vf->{chr}." on line ".$config->{line_number}."\n") unless defined $config->{quiet};
-                            next;
-                        }
-
-                        # store the hash
-                        $slice_cache{$vf->{chr}} = $slice;
-                    }
-                }
-
-                $vf->{slice} = $slice;
-            }
-
-            # validate the VF
-            next unless validate_vf($config, $vf);
-
-            # make a name if one doesn't exist
-            $vf->{variation_name} ||= $vf->{chr}.'_'.$vf->{start}.'_'.$vf->{allele_string};
-
-            # jump out to convert here
-            if(defined($config->{convert})) {
-                &convert_vf($config, $vf);
-                next;
-            }
-
-            if(defined $config->{whole_genome}) {
-                push @vfs, $vf;
-                $vf_count++;
-                $total_vf_count++;
-
-                if($vf_count == $config->{buffer_size}) {
-                    debug("Read $vf_count variants into buffer") unless defined($config->{quiet});
-
-                    print_line($config, $_) foreach @{get_all_consequences($config, \@vfs, $tr_cache, $rf_cache)};
-
-                    debug("Processed $total_vf_count total variants") unless defined($config->{quiet});
-
-                    @vfs = ();
-                    $vf_count = 0;
-                }
-            }
-            else {
-                print_line($config, $_) foreach @{vf_to_consequences($config, $vf)};
-                $vf_count++;
-                $total_vf_count++;
-                debug("Processed $vf_count variants") if $vf_count =~ /0$/ && defined($config->{verbose});
-            }
-        }
-    }
-
-    # if in whole-genome mode, finish off the rest of the buffer
-    if(defined $config->{whole_genome} && scalar @vfs) {
-        debug("Read $vf_count variants into buffer") unless defined($config->{quiet});
-
-        print_line($config, $_) foreach @{get_all_consequences($config, \@vfs, $tr_cache, $rf_cache)};
-
-        debug("Processed $total_vf_count total variants") unless defined($config->{quiet});
-
-        debug($config->{filter_count}, "/$total_vf_count variants remain after filtering") if defined($config->{filter}) && !defined($config->{quiet});
-    }
-
-    debug("Executed ", defined($Bio::EnsEMBL::DBSQL::StatementHandle::count_queries) ? $Bio::EnsEMBL::DBSQL::StatementHandle::count_queries : 'unknown number of', " SQL statements") if defined($config->{count_queries}) && !defined($config->{quiet});
-
-    debug("Finished!") unless defined $config->{quiet};
-
-
-    use Data::Dumper;
-    $Data::Dumper::Maxdepth = 3;
-    open OUT, ">module.list.vep"; print OUT Dumper \%INC; close OUT;
-}
-
-# sets up configuration hash that is used throughout the script
-sub configure {
-    my $args = shift;
-
-    my $config = {};
-
-    GetOptions(
-        $config,
-        'help',                    # displays help message
-
-        # input options,
-        'config=s',                # config file name
-        'input_file|i=s',          # input file name
-        'format=s',                # input file format
-
-        # DB options
-        'species=s',               # species e.g. human, homo_sapiens
-        'registry=s',              # registry file
-        'host=s',                  # database host
-        'port=s',                  # database port
-        'user=s',                  # database user name
-        'password=s',              # database password
-        'db_version=i',            # Ensembl database version to use e.g. 62
-        'genomes',                 # automatically sets DB params for e!Genomes
-        'refseq',                  # use otherfeatures RefSeq DB instead of Ensembl
-        #'no_disconnect',           # disables disconnect_when_inactive
-
-        # runtime options
-        'most_severe',             # only return most severe consequence
-        'summary',                 # only return one line per variation with all consquence types
-        'per_gene',                # only return most severe per gene
-        'buffer_size=i',           # number of variations to read in before analysis
-        'chunk_size=s',            # size in bases of "chunks" used in internal hash structure
-        'failed=i',                # include failed variations when finding existing
-        'no_whole_genome',         # disables now default whole-genome mode
-        'whole_genome',            # proxy for whole genome mode - now just warns user
-        'gp',                      # read coords from GP part of INFO column in VCF (probably only relevant to 1KG)
-        'chr=s',                   # analyse only these chromosomes, e.g. 1-5,10,MT
-        'check_ref',               # check supplied reference allele against DB
-        'check_existing',          # find existing co-located variations
-        'check_alleles',           # only attribute co-located if alleles are the same
-        'check_frequency',         # enable frequency checking
-        'freq_filter=s',           # exclude or include
-        'freq_freq=f',             # frequency to filter on
-        'freq_gt_lt=s',            # gt or lt (greater than or less than)
-        'freq_pop=s',              # population to filter on
-
-        # verbosity options
-        'verbose|v',               # print out a bit more info while running
-        'quiet',                   # print nothing to STDOUT (unless using -o stdout)
-        'no_progress',             # don't display progress bars
-
-        # output options
-        'output_file|o=s',         # output file name
-        'force_overwrite',         # force overwrite of output file if already exists
-        'terms=s',                 # consequence terms to use e.g. NCBI, SO
-        'coding_only',             # only return results for consequences in coding regions
-        'canonical',               # indicates if transcript is canonical
-        'ccds',                    # output CCDS identifer
-        'xref_refseq',             # output refseq mrna xref
-        'protein',                 # add e! protein ID to extra column
-        'hgnc',                    # add HGNC gene ID to extra column
-        'hgvs',                    # add HGVS names to extra column
-        'sift=s',                  # SIFT predictions
-        'polyphen=s',              # PolyPhen predictions
-        'condel=s',                # Condel predictions
-        'gene',                    # force gene column to be populated (disabled by default, enabled when using cache)
-        'regulatory',              # enable regulatory stuff
-        'convert=s',               # convert input to another format (doesn't run VEP)
-        'filter=s',                # run in filtering mode
-        'no_intergenic',           # don't print out INTERGENIC consequences
-        'gvf',                     # produce gvf output
-        'vcf',                     # produce vcf output
-        'original',                # produce output in input format
-        'no_consequences',         # don't calculate consequences
-        'lrg',                     # enable LRG-based features
-        'fields=s',                # define your own output fields
-
-        # cache stuff
-        'cache',                   # use cache
-        'write_cache',             # enables writing to the cache
-        'build=s',                 # builds cache from DB from scratch; arg is either all (all top-level seqs) or a list of chrs
-        'no_adaptor_cache',        # don't write adaptor cache
-        'prefetch',                # prefetch exons, translation, introns, codon table etc for each transcript
-        'strip',                   # strips adaptors etc from objects before caching them
-        'rebuild=s',               # rebuilds cache by reading in existing then redumping - probably don't need to use this any more
-        'dir=s',                   # dir where cache is found (defaults to $HOME/.vep/)
-        'cache_region_size=i',     # size of region in bases for each cache file
-        'no_slice_cache',          # tell API not to cache features on slice
-        'standalone',              # standalone mode uses minimal set of modules installed in same dir, no DB connection
-        'skip_db_check',           # don't compare DB parameters with cached
-        'compress=s',              # by default we use zcat to decompress; user may want to specify gzcat or "gzip -dc"
-        'custom=s' => ($config->{custom} ||= []), # specify custom tabixed bgzipped file with annotation
-        'tmpdir=s',                # tmp dir used for BigWig retrieval
-        'plugin=s' => ($config->{plugin} ||= []), # specify a method in a module in the plugins directory
-
-        # debug
-        'cluck',                   # these two need some mods to Bio::EnsEMBL::DBSQL::StatementHandle to work. Clucks callback trace and SQL
-        'count_queries',           # counts SQL queries executed
-        'admin',                   # allows me to build off public hosts
-        'debug',                   # print out debug info
-    );
-
-    # print usage message if requested or no args supplied
-    if(defined($config->{help}) || !$args) {
-        &usage;
-        exit(0);
-    }
-
-    # dir is where the cache and plugins live
-    $config->{dir} ||= join '/', ($ENV{'HOME'}, '.vep');
-
-    # ini file?
-    my $ini_file = $config->{dir}.'/vep.ini';
-
-    if(-e $ini_file) {
-        read_config_from_file($config, $ini_file);
-    }
-
-    # config file?
-    if(defined $config->{config}) {
-        read_config_from_file($config, $config->{config});
-    }
-
-    # can't be both quiet and verbose
-    die "ERROR: Can't be both quiet and verbose!\n" if defined($config->{quiet}) && defined($config->{verbose});
-
-    # check file format
-    if(defined $config->{format}) {
-        die "ERROR: Unrecognised input format specified \"".$config->{format}."\"\n" unless $config->{format} =~ /pileup|vcf|guess|hgvs|ensembl|id|vep/i;
-    }
-
-    # check convert format
-    if(defined $config->{convert}) {
-        die "ERROR: Unrecognised output format for conversion specified \"".$config->{convert}."\"\n" unless $config->{convert} =~ /vcf|ensembl|pileup|hgvs/i;
-    }
-
-    # connection settings for Ensembl Genomes
-    if($config->{genomes}) {
-        $config->{host} ||= 'mysql.ebi.ac.uk';
-        $config->{port} ||= 4157;
-    }
-
-    # connection settings for main Ensembl
-    else {
-        $config->{species} ||= "homo_sapiens";
-        $config->{host}    ||= 'ensembldb.ensembl.org';
-        $config->{port}    ||= 5306;
-    }
-
-    # refseq or core?
-    if(defined($config->{refseq})) {
-        die "ERROR: SIFT, PolyPhen and Condel predictions not available fore RefSeq transcripts\n" if defined $config->{sift} || defined $config->{polyphen} || defined $config->{condel};
-
-        $config->{core_type} = 'otherfeatures';
-    }
-    else {
-        $config->{core_type} = 'core';
-    }
-
-    # output term
-    if(defined $config->{terms}) {
-        die "ERROR: Unrecognised consequence term type specified \"".$config->{terms}."\" - must be one of ensembl, so, ncbi\n" unless $config->{terms} =~ /ensembl|display|so|ncbi/i;
-        if($config->{terms} =~ /ensembl|display/i) {
-            $config->{terms} = 'display';
-        }
-        else {
-            $config->{terms} = uc($config->{terms});
-        }
-    }
-
-    # check nsSNP tools
-    foreach my $tool(grep {defined $config->{lc($_)}} qw(SIFT PolyPhen Condel)) {
-        die "ERROR: Unrecognised option for $tool \"", $config->{lc($tool)}, "\" - must be one of p (prediction), s (score) or b (both)\n" unless $config->{lc($tool)} =~ /^(s|p|b)/;
-
-        die "ERROR: $tool not available for this species\n" unless $config->{species} =~ /human|homo/i;
-
-        # use V2 of the Condel algorithm, possibly gives fewer false positives
-        if($tool eq 'Condel' && $config->{lc($tool)} =~ /1$/) {
-            $Bio::EnsEMBL::Variation::Utils::Condel::USE_V2 = 0;
-        }
-    }
-
-    # force quiet if outputting to STDOUT
-    if(defined($config->{output_file}) && $config->{output_file} =~ /stdout/i) {
-        delete $config->{verbose} if defined($config->{verbose});
-        $config->{quiet} = 1;
-    }
-
-    # summarise options if verbose
-    if(defined $config->{verbose}) {
-        my $header =<<INTRO;
-#----------------------------------#
-# ENSEMBL VARIANT EFFECT PREDICTOR #
-#----------------------------------#
-
-version $VERSION
-
-By Will McLaren (wm2\@ebi.ac.uk)
-
-Configuration options:
-
-INTRO
-        print $header;
-
-        my $max_length = (sort {$a <=> $b} map {length($_)} keys %$config)[-1];
-
-        foreach my $key(sort keys %$config) {
-            next if ref($config->{$key}) eq 'ARRAY' && scalar @{$config->{$key}} == 0;
-            print $key.(' ' x (($max_length - length($key)) + 4)).(ref($config->{$key}) eq 'ARRAY' ? join "\t", @{$config->{$key}} : $config->{$key})."\n";
-        }
-
-        print "\n".("-" x 20)."\n\n";
-    }
-
-    # check custom annotations
-    for my $i(0..$#{$config->{custom}}) {
-        my $custom = $config->{custom}->[$i];
-
-        my ($filepath, $shortname, $format, $type, $coords) = split /\,/, $custom;
-        $type ||= 'exact';
-        $format ||= 'bed';
-        $coords ||= 0;
-
-        # check type
-        die "ERROR: Type $type for custom annotation file $filepath is not allowed (must be one of \"exact\", \"overlap\")\n" unless $type =~ /exact|overlap/;
-
-        # check format
-        die "ERROR: Format $format for custom annotation file $filepath is not allowed (must be one of \"bed\", \"vcf\", \"gtf\", \"gff\", \"bigwig\")\n" unless $format =~ /bed|vcf|gff|gtf|bigwig/;
-
-        # bigwig format
-        if($format eq 'bigwig') {
-            # check for bigWigToWig
-            die "ERROR: bigWigToWig does not seem to be in your path - this is required to use bigwig format custom annotations\n" unless `which bigWigToWig 2>&1` =~ /bigWigToWig$/;
-        }
-
-        else {
-            # check for tabix
-            die "ERROR: tabix does not seem to be in your path - this is required to use custom annotations\n" unless `which tabix 2>&1` =~ /tabix$/;
-
-            # remote files?
-            if($filepath =~ /tp\:\/\//) {
-                my $remote_test = `tabix $filepath 1:1-1 2>&1`;
-                if($remote_test =~ /fail/) {
-                    die "$remote_test\nERROR: Could not find file or index file for remote annotation file $filepath\n";
-                }
-                elsif($remote_test =~ /get_local_version/) {
-                    debug("Downloaded tabix index file for remote annotation file $filepath") unless defined($config->{quiet});
-                }
-            }
-
-            # check files exist
-            else {
-                die "ERROR: Custom annotation file $filepath not found\n" unless -e $filepath;
-                die "ERROR: Tabix index file $filepath\.tbi not found - perhaps you need to create it first?\n" unless -e $filepath.'.tbi';
-            }
-        }
-
-        $config->{custom}->[$i] = {
-            'file'   => $filepath,
-            'name'   => $shortname || 'CUSTOM'.($i + 1),
-            'type'   => $type,
-            'format' => $format,
-            'coords' => $coords,
-        };
-    }
-
-    # check if using filter and original
-    die "ERROR: You must also provide output filters using --filter to use --original\n" if defined($config->{original}) && !defined($config->{filter});
-
-    # filter by consequence?
-    if(defined($config->{filter})) {
-
-        my %filters = map {$_ => 1} split /\,/, $config->{filter};
-
-        # add in shortcuts
-        foreach my $filter(keys %filters) {
-            my $value = 1;
-            if($filter =~ /^no_/) {
-                delete $filters{$filter};
-                $filter =~ s/^no_//g;
-                $value = 0;
-                $filters{$filter} = $value;
-            }
-
-            if(defined($FILTER_SHORTCUTS{$filter})) {
-                delete $filters{$filter};
-                $filters{$_} = $value for keys %{$FILTER_SHORTCUTS{$filter}};
-            }
-        }
-
-        $config->{filter} = \%filters;
-
-        $config->{filter_count} = 0;
-    }
-
-    # set defaults
-    $config->{user}              ||= 'anonymous';
-    $config->{buffer_size}       ||= 5000;
-    $config->{chunk_size}        ||= '50kb';
-    $config->{output_file}       ||= "variant_effect_output.txt";
-    $config->{tmpdir}            ||= '/tmp';
-    $config->{format}            ||= 'guess';
-    $config->{terms}             ||= 'display';
-    $config->{gene}              ||= 1 unless defined($config->{whole_genome}) && !defined($config->{cache});
-    $config->{cache_region_size} ||= 1000000;
-    $config->{compress}          ||= 'zcat';
-    $config->{tmpdir}            ||= '/tmp';
-
-    # frequency filtering
-    if(defined($config->{check_frequency})) {
-        foreach my $flag(qw(freq_freq freq_filter freq_pop freq_gt_lt)) {
-            die "ERROR: To use --check_frequency you must also specify flag --$flag\n" unless defined $config->{$flag};
-        }
-
-        # need to set check_existing
-        $config->{check_existing} = 1;
-    }
-
-    $config->{check_existing} = 1 if defined $config->{check_alleles};
-
-    # warn users still using whole_genome flag
-    if(defined($config->{whole_genome})) {
-        debug("INFO: Whole-genome mode is now the default run-mode for the script. To disable it, use --no_whole_genome") unless defined($config->{quiet});
-    }
-
-    $config->{whole_genome}      = 1 unless defined $config->{no_whole_genome};
-    $config->{failed}            = 0 unless defined $config->{failed};
-    $config->{chunk_size}        =~ s/mb?/000000/i;
-    $config->{chunk_size}        =~ s/kb?/000/i;
-    $config->{cache_region_size} =~ s/mb?/000000/i;
-    $config->{cache_region_size} =~ s/kb?/000/i;
-
-    # cluck and display executed SQL?
-    $Bio::EnsEMBL::DBSQL::StatementHandle::cluck = 1 if defined($config->{cluck});
-
-    # standalone needs cache, can't use HGVS
-    if(defined($config->{standalone})) {
-        $config->{cache} = 1;
-
-        die("ERROR: Cannot generate HGVS coordinates in standalone mode\n") if defined($config->{hgvs});
-        die("ERROR: Cannot use HGVS as input in standalone mode\n") if $config->{format} eq 'hgvs';
-        die("ERROR: Cannot use variant identifiers as input in standalone mode\n") if $config->{format} eq 'id';
-        die("ERROR: Cannot do frequency filtering in standalone mode\n") if defined($config->{check_frequency});
-    }
-
-    # write_cache needs cache
-    $config->{cache} = 1 if defined $config->{write_cache};
-
-    # no_slice_cache, prefetch and whole_genome have to be on to use cache
-    if(defined($config->{cache})) {
-        $config->{prefetch} = 1;
-        $config->{no_slice_cache} = 1;
-        $config->{whole_genome} = 1;
-        $config->{strip} = 1;
-    }
-
-    $config->{build} = $config->{rebuild} if defined($config->{rebuild});
-
-    # force options for full build
-    if(defined($config->{build})) {
-        $config->{prefetch} = 1;
-        $config->{gene} = 1;
-        $config->{hgnc} = 1;
-        $config->{no_slice_cache} = 1;
-        $config->{cache} = 1;
-        $config->{strip} = 1;
-        $config->{write_cache} = 1;
-    }
-
-    # connect to databases
-    $config->{reg} = &connect_to_dbs($config);
-
-    # complete dir with species name and db_version
-    $config->{dir} .= '/'.(
-        join '/', (
-            defined($config->{standalone}) ? $config->{species} : ($config->{reg}->get_alias($config->{species}) || $config->{species}),
-            $config->{db_version} || $config->{reg}->software_version
-        )
-    );
-
-    # warn user cache directory doesn't exist
-    if(!-e $config->{dir}) {
-
-        # if using write_cache
-        if(defined($config->{write_cache})) {
-            debug("INFO: Cache directory ", $config->{dir}, " not found - it will be created") unless defined($config->{quiet});
-        }
-
-        # want to read cache, not found
-        elsif(defined($config->{cache})) {
-            die("ERROR: Cache directory ", $config->{dir}, " not found");
-        }
-    }
-
-    if(defined($config->{cache})) {
-        # read cache info
-        if(read_cache_info($config)) {
-            debug("Read existing cache info") unless defined $config->{quiet};
-        }
-    }
-
-    # we configure plugins here because they can sometimes switch on the
-    # regulatory config option
-    configure_plugins($config);
-
-    # include regulatory modules if requested
-    if(defined($config->{regulatory})) {
-        # do the use statements here so that users don't have to have the
-        # funcgen API installed to use the rest of the script
-        eval q{
-            use Bio::EnsEMBL::Funcgen::DBSQL::RegulatoryFeatureAdaptor;
-            use Bio::EnsEMBL::Funcgen::DBSQL::MotifFeatureAdaptor;
-            use Bio::EnsEMBL::Funcgen::MotifFeature;
-            use Bio::EnsEMBL::Funcgen::RegulatoryFeature;
-            use Bio::EnsEMBL::Funcgen::BindingMatrix;
-        };
-
-        if($@) {
-            die("ERROR: Ensembl Funcgen API must be installed to use --regulatory or plugins that deal with regulatory features\n");
-        }
-    }
-
-    # user defined custom output fields
-    if(defined($config->{fields})) {
-        $config->{fields} = [split ',', $config->{fields}];
-        debug("Output fields redefined (".scalar @{$config->{fields}}." defined)") unless defined($config->{quiet});
-    }
-    $config->{fields} ||= \@OUTPUT_COLS;
-
-    # suppress warnings that the FeatureAdpators spit if using no_slice_cache
-    Bio::EnsEMBL::Utils::Exception::verbose(1999) if defined($config->{no_slice_cache});
-
-    # get adaptors (don't get them in standalone mode)
-    unless(defined($config->{standalone})) {
-
-        if(defined($config->{cache}) && !defined($config->{write_cache})) {
-
-            # try and load adaptors from cache
-            if(!&load_dumped_adaptor_cache($config)) {
-                &get_adaptors($config);
-                &dump_adaptor_cache($config) if defined($config->{write_cache}) && !defined($config->{no_adaptor_cache});
-            }
-
-            # check cached adaptors match DB params
-            else {
-                my $dbc = $config->{sa}->{dbc};
-
-                my $ok = 1;
-
-                if($dbc->{_host} ne $config->{host}) {
-
-                    # ens-livemirror, useastdb and ensembldb should all have identical DBs
-                    unless(
-                        (
-                            $dbc->{_host} eq 'ens-livemirror'
-                            || $dbc->{_host} eq 'ensembldb.ensembl.org'
-                            || $dbc->{_host} eq 'useastdb.ensembl.org'
-                        ) && (
-                            $config->{host} eq 'ens-livemirror'
-                            || $config->{host} eq 'ensembldb.ensembl.org'
-                            || $config->{host} eq 'useastdb.ensembl.org'
-                        )
-                    ) {
-                        $ok = 0;
-                    }
-
-                    unless(defined($config->{skip_db_check})) {
-                        # but we still need to reconnect
-                        debug("INFO: Defined host ", $config->{host}, " is different from cached ", $dbc->{_host}, " - reconnecting to host") unless defined($config->{quiet});
-
-                        &get_adaptors($config);
-                    }
-                }
-
-                if(!$ok) {
-                    if(defined($config->{skip_db_check})) {
-                        debug("INFO: Defined host ", $config->{host}, " is different from cached ", $dbc->{_host}) unless defined($config->{quiet});
-                    }
-                    else {
-                        die "ERROR: Defined host ", $config->{host}, " is different from cached ", $dbc->{_host}, ". If you are sure this is OK, rerun with -skip_db_check flag set";
-                    }
-                }
-            }
-        }
-        else {
-            &get_adaptors($config);
-            &dump_adaptor_cache($config) if defined($config->{write_cache}) && !defined($config->{no_adaptor_cache});
-        }
-
-        # reg adaptors (only fetches if not retrieved from cache already)
-        &get_reg_adaptors($config) if defined($config->{regulatory});
-    }
-
-    # get terminal width for progress bars
-    unless(defined($config->{quiet})) {
-        my $width;
-
-        # module may not be installed
-        eval q{
-            use Term::ReadKey;
-        };
-
-        if(!$@) {
-            my ($w, $h);
-
-            # module may be installed, but e.g.
-            eval {
-                ($w, $h) = GetTerminalSize();
-            };
-
-            $width = $w if defined $w;
-        }
-
-        $width ||= 60;
-        $width -= 12;
-        $config->{terminal_width} = $width;
-    }
-
-    # jump out to build cache if requested
-    if(defined($config->{build})) {
-
-        if($config->{host} =~ /^(ensembl|useast)db\.ensembl\.org$/ && !defined($config->{admin})) {
-            die("ERROR: Cannot build cache using public database server ", $config->{host}, "\n");
-        }
-
-        # build the cache
-        debug("Building cache for ".$config->{species}) unless defined($config->{quiet});
-        build_full_cache($config);
-
-        # exit script
-        debug("Finished building cache") unless defined($config->{quiet});
-        exit(0);
-    }
-
-
-    # warn user DB will be used for SIFT/PolyPhen/Condel/HGVS/frequency/LRG
-    if(defined($config->{cache})) {
-
-        # these two def depend on DB
-        foreach my $param(grep {defined $config->{$_}} qw(hgvs check_frequency lrg)) {
-            debug("INFO: Database will be accessed when using --$param") unless defined($config->{quiet});
-        }
-
-        # as does using HGVS or IDs as input
-        debug("INFO: Database will be accessed when using --format ", $config->{format}) if ($config->{format} eq 'id' || $config->{format} eq 'hgvs') && !defined($config->{quiet});
-
-        # the rest may be in the cache
-        foreach my $param(grep {defined $config->{$_}} qw(sift polyphen condel regulatory)) {
-            next if defined($config->{'cache_'.$param});
-            debug("INFO: Database will be accessed when using --$param; consider using the complete cache containing $param data (see documentation for details)") unless defined($config->{quiet});
-        }
-    }
-
-    # get list of chrs if supplied
-    if(defined($config->{chr})) {
-        my %chrs;
-
-        foreach my $val(split /\,/, $config->{chr}) {
-            my @nnn = split /\-/, $val;
-
-            foreach my $chr($nnn[0]..$nnn[-1]) {
-                $chrs{$chr} = 1;
-            }
-        }
-
-        $config->{chr} = \%chrs;
-    }
-
-    # get input file handle
-    $config->{in_file_handle} = &get_in_file_handle($config);
-
-    return $config;
-}
-
-# reads config from a file
-sub read_config_from_file {
-    my $config = shift;
-    my $file = shift;
-
-    open CONFIG, $file or die "ERROR: Could not open config file \"$file\"\n";
-
-    debug("Reading configuration from $file") unless defined($config->{quiet});
-
-    while(<CONFIG>) {
-        next if /^\#/;
-        my @split = split /\s+|\=/;
-        my $key = shift @split;
-        $key =~ s/^\-//g;
-
-        if(defined($config->{$key}) && ref($config->{$key}) eq 'ARRAY') {
-            push @{$config->{$key}}, @split;
-        }
-        else {
-            $config->{$key} ||= $split[0];
-        }
-    }
-
-    close CONFIG;
-}
-
-# configures custom VEP plugins
-sub configure_plugins {
-
-    my $config = shift;
-
-    $config->{plugins} = [];
-
-    if (my @plugins = @{ $config->{plugin} }) {
-
-        use lib "$ENV{HOME}/.vep/Plugins";
-
-        for my $plugin (@plugins) {
-
-            # parse out the module name and parameters
-
-            my ($module, @params) = split /,/, $plugin;
-
-            # check we can use the module
-
-            eval qq{
-                use $module;
-            };
-            if ($@) {
-                die "Failed to compile plugin $module: $@";
-            }
-
-            # now check we can instantiate it, passing any parameters to the constructor
-
-            my $instance;
-
-            eval {
-                $instance = $module->new($config, @params);
-            };
-            if ($@) {
-                die "Failed to instantiate plugin $module: $@";
-            }
-
-            # check that the versions match
-
-            my $plugin_version;
-
-            if ($instance->can('version')) {
-                $plugin_version = $instance->version;
-            }
-
-            my $version_ok = 1;
-
-            if ($plugin_version) {
-                my ($plugin_major, $plugin_minor, $plugin_maintenance) = split /\./, $plugin_version;
-                my ($major, $minor, $maintenance) = split /\./, $VERSION;
-
-                if ($plugin_major != $major) {
-                    warn "Warning: plugin $plugin version ($plugin_version) does not match the current VEP version ($VERSION).\n";
-                    $version_ok = 0;
-                }
-            }
-            else {
-                warn "Warning: plugin $plugin does not define a version number.\n";
-                $version_ok = 0;
-            }
-
-            warn "You may experience unexpected behaviour with this plugin.\n" unless $version_ok;
-
-            # check that it implements all necessary methods
-
-            for my $required(qw(run get_header_info check_feature_type check_variant_feature_type)) {
-                unless ($instance->can($required)) {
-                    die "Plugin $module doesn't implement a required method '$required', does it inherit from BaseVepPlugin?";
-                }
-            }
-
-            # all's good, so save the instance in our list of plugins
-
-            push @{ $config->{plugins} }, $instance;
-
-            debug("Loaded plugin: $module");
-
-            # for convenience, check if the plugin wants regulatory stuff and turn on the config option if so
-
-            if (grep { $_ =~ /motif|regulatory/i } @{ $instance->feature_types }) {
-                debug("Fetching regulatory features for plugin: $module");
-                $config->{regulatory} = 1;
-            }
-        }
-    }
-}
-
-# connects to DBs (not done in standalone mode)
-sub connect_to_dbs {
-    my $config = shift;
-
-    # get registry
-    my $reg = 'Bio::EnsEMBL::Registry';
-
-    unless(defined($config->{standalone})) {
-        # load DB options from registry file if given
-        if(defined($config->{registry})) {
-            debug("Loading DB config from registry file ", $config->{registry}) unless defined($config->{quiet});
-            $reg->load_all(
-                $config->{registry},
-                $config->{verbose},
-                undef,
-                $config->{no_slice_cache}
-            );
-        }
-
-        # otherwise manually connect to DB server
-        else {
-            $reg->load_registry_from_db(
-                -host       => $config->{host},
-                -user       => $config->{user},
-                -pass       => $config->{password},
-                -port       => $config->{port},
-                -db_version => $config->{db_version},
-                -species    => $config->{species} =~ /^[a-z]+\_[a-z]+/i ? $config->{species} : undef,
-                -verbose    => $config->{verbose},
-                -no_cache   => $config->{no_slice_cache},
-            );
-        }
-
-        eval { $reg->set_reconnect_when_lost() };
-
-        if(defined($config->{verbose})) {
-            # get a meta container adaptors to check version
-            my $core_mca = $reg->get_adaptor($config->{species}, 'core', 'metacontainer');
-            my $var_mca = $reg->get_adaptor($config->{species}, 'variation', 'metacontainer');
-
-            if($core_mca && $var_mca) {
-                debug(
-                    "Connected to core version ", $core_mca->get_schema_version, " database ",
-                    "and variation version ", $var_mca->get_schema_version, " database"
-                );
-            }
-        }
-    }
-
-    return $reg;
-}
-
-# get adaptors from DB
-sub get_adaptors {
-    my $config = shift;
-
-    die "ERROR: No registry" unless defined $config->{reg};
-
-    $config->{vfa}   = $config->{reg}->get_adaptor($config->{species}, 'variation', 'variationfeature');
-    $config->{svfa}  = $config->{reg}->get_adaptor($config->{species}, 'variation', 'structuralvariationfeature');
-    $config->{tva}   = $config->{reg}->get_adaptor($config->{species}, 'variation', 'transcriptvariation');
-    $config->{pfpma} = $config->{reg}->get_adaptor($config->{species}, 'variation', 'proteinfunctionpredictionmatrix');
-    $config->{va}    = $config->{reg}->get_adaptor($config->{species}, 'variation', 'variation');
-
-    # get fake ones for species with no var DB
-    if(!defined($config->{vfa})) {
-        $config->{vfa}  = Bio::EnsEMBL::Variation::DBSQL::VariationFeatureAdaptor->new_fake($config->{species});
-        $config->{svfa} = Bio::EnsEMBL::Variation::DBSQL::StructuralVariationFeatureAdaptor->new_fake($config->{species});
-        $config->{tva}  = Bio::EnsEMBL::Variation::DBSQL::TranscriptVariationAdaptor->new_fake($config->{species});
-    }
-
-    $config->{sa}  = $config->{reg}->get_adaptor($config->{species}, $config->{core_type}, 'slice');
-    $config->{ga}  = $config->{reg}->get_adaptor($config->{species}, $config->{core_type}, 'gene');
-    $config->{ta}  = $config->{reg}->get_adaptor($config->{species}, $config->{core_type}, 'transcript');
-    $config->{mca} = $config->{reg}->get_adaptor($config->{species}, $config->{core_type}, 'metacontainer');
-    $config->{csa} = $config->{reg}->get_adaptor($config->{species}, $config->{core_type}, 'coordsystem');
-
-    # cache schema version
-    $config->{mca}->get_schema_version if defined $config->{mca};
-
-    # check we got slice adaptor - can't continue without a core DB
-    die("ERROR: Could not connect to core database\n") unless defined $config->{sa};
-}
-
-# gets regulatory adaptors
-sub get_reg_adaptors {
-    my $config = shift;
-
-    foreach my $type(@REG_FEAT_TYPES) {
-        next if defined($config->{$type.'_adaptor'});
-
-        my $adaptor = $config->{reg}->get_adaptor($config->{species}, 'funcgen', $type);
-        if(defined($adaptor)) {
-            $config->{$type.'_adaptor'} = $adaptor;
-        }
-        else {
-            delete $config->{regulatory};
-            last;
-        }
-    }
-}
-
-# gets file handle for input
-sub get_in_file_handle {
-    my $config = shift;
-
-    # define the filehandle to read input from
-    my $in_file_handle = new FileHandle;
-
-    if(defined($config->{input_file})) {
-
-        # check defined input file exists
-        die("ERROR: Could not find input file ", $config->{input_file}, "\n") unless -e $config->{input_file};
-
-        if($config->{input_file} =~ /\.gz$/){
-            $in_file_handle->open($config->{compress}." ". $config->{input_file} . " | " ) or die("ERROR: Could not read from input file ", $config->{input_file}, "\n");
-        }
-        else {
-            $in_file_handle->open( $config->{input_file} ) or die("ERROR: Could not read from input file ", $config->{input_file}, "\n");
-        }
-    }
-
-    # no file specified - try to read data off command line
-    else {
-        $in_file_handle = 'STDIN';
-        debug("Reading input from STDIN (or maybe you forgot to specify an input file?)...") unless defined $config->{quiet};
-    }
-
-    return $in_file_handle;
-}
-
-# gets file handle for output and adds header
-sub get_out_file_handle {
-    my $config = shift;
-
-    # define filehandle to write to
-    my $out_file_handle = new FileHandle;
-
-    # check if file exists
-    if(-e $config->{output_file} && !defined($config->{force_overwrite})) {
-        die("ERROR: Output file ", $config->{output_file}, " already exists. Specify a different output file with --output_file or overwrite existing file with --force_overwrite\n");
-    }
-
-    if($config->{output_file} =~ /stdout/i) {
-        $out_file_handle = *STDOUT;
-    }
-    else {
-        $out_file_handle->open(">".$config->{output_file}) or die("ERROR: Could not write to output file ", $config->{output_file}, "\n");
-    }
-
-    # define headers for a VCF file
-    my @vcf_headers = (
-        '#CHROM',
-        'POS',
-        'ID',
-        'REF',
-        'ALT',
-        'QUAL',
-        'FILTER',
-        'INFO'
-    );
-
-    # file conversion, don't want to add normal headers
-    if(defined($config->{convert})) {
-        # header for VCF
-        if($config->{convert} =~ /vcf/i) {
-            print $out_file_handle "##fileformat=VCFv4.0\n";
-            print $out_file_handle join "\t", @vcf_headers;
-            print $out_file_handle "\n";
-        }
-
-        return $out_file_handle;
-    }
-
-    # GVF output, no header
-    elsif(defined($config->{gvf}) || defined($config->{original})) {
-        print $out_file_handle join "\n", @{$config->{headers}} if defined($config->{headers}) && defined($config->{original});
-        return $out_file_handle;
-    }
-
-    elsif(defined($config->{vcf})) {
-
-        # create an info string for the VCF header
-        my @vcf_info_strings = ('##INFO=<ID=CSQ,Number=.,Type=String,Description="Consequence type as predicted by VEP">');
-
-        # add custom headers
-        foreach my $custom(@{$config->{custom}}) {
-            push @vcf_info_strings, '##INFO=<ID='.$custom->{name}.',Number=.,Type=String,Description="'.$custom->{file}.' ('.$custom->{type}.')">';
-        }
-
-        # can't use plugins on VCF output yet
-        # plugin headers
-        #my $plugin_header = get_plugin_headers($config);
-        #if(defined($plugin_header)) {
-        #    $plugin_header =~ s/\n$//g;
-        #    push @vcf_info_strings, $plugin_header;
-        #}
-
-        # if this is already a VCF file, we need to add extra headers in the right place
-        if(defined($config->{headers})) {
-
-            for my $i(0..$#{$config->{headers}}) {
-                if($config->{headers}->[$i] =~ /^\#CHROM\s+POS\s+ID/) {
-                    splice(@{$config->{headers}}, $i, 0, @vcf_info_strings);
-                }
-            }
-
-            print $out_file_handle join "\n", @{$config->{headers}};
-            print $out_file_handle "\n";
-        }
-
-        else {
-            print $out_file_handle "##fileformat=VCFv4.0\n";
-            print $out_file_handle join "\n", @vcf_info_strings;
-            print $out_file_handle "\n";
-            print $out_file_handle join "\t", @vcf_headers;
-            print $out_file_handle "\n";
-        }
-
-        return $out_file_handle;
-    }
-
-    # make header
-    my $time = &get_time;
-    my $db_string = $config->{mca}->dbc->dbname." on ".$config->{mca}->dbc->host if defined $config->{mca};
-    $db_string .= "\n## Using cache in ".$config->{dir} if defined($config->{cache});
-    my $version_string =
-        "Using API version ".$config->{reg}->software_version.
-        ", DB version ".(defined $config->{mca} && $config->{mca}->get_schema_version ? $config->{mca}->get_schema_version : '?');
-
-    my $header =<<HEAD;
-## ENSEMBL VARIANT EFFECT PREDICTOR v$VERSION
-## Output produced at $time
-## Connected to $db_string
-## $version_string
-## Extra column keys:
-## CANONICAL    : Indicates if transcript is canonical for this gene
-## CCDS         : Indicates if transcript is a CCDS transcript
-## HGNC         : HGNC gene identifier
-## ENSP         : Ensembl protein identifer
-## HGVSc        : HGVS coding sequence name
-## HGVSp        : HGVS protein sequence name
-## SIFT         : SIFT prediction
-## PolyPhen     : PolyPhen prediction
-## Condel       : Condel SIFT/PolyPhen consensus prediction
-## MATRIX       : The source and identifier of a transcription factor binding profile (TFBP) aligned at this position
-## MATRIX_POS   : The relative position of the variation in the aligned TFBP
-## HIGH_INF_POS : A flag indicating if the variant falls in a high information position of the TFBP
-## MOTIF_SCORE_DELTA : The difference in motif score of the reference and variant sequences for the TFBP
-HEAD
-
-    $header .= get_plugin_headers($config);
-
-    # add headers
-    print $out_file_handle $header;
-
-    # add custom data defs
-    if(defined($config->{custom})) {
-        foreach my $custom(@{$config->{custom}}) {
-            print $out_file_handle '## '.$custom->{name}."\t: ".$custom->{file}.' ('.$custom->{type}.")\n";
-        }
-    }
-
-    # add column headers
-    print $out_file_handle '#', (join "\t", @{$config->{fields}});
-    print $out_file_handle "\n";
-
-    return $out_file_handle;
-}
-
-sub get_plugin_headers {
-
-    my $config = shift;
-
-    my $header = "";
-
-    for my $plugin (@{ $config->{plugins} }) {
-        if (my $hdr = $plugin->get_header_info) {
-            for my $key (keys %$hdr) {
-                my $val = $hdr->{$key};
-
-                if($config->{vcf}) {
-                    $header .= '##INFO=<ID='.$key.',Number=.,Type=String,Description="'.$val.'">'."\n";
-                }
-                else {
-                    $header .= "## $key\t: $val\n";
-                }
-            }
-        }
-    }
-
-    return $header;
-}
-
-# convert a variation feature to a line of output
-sub convert_vf {
-    my $config = shift;
-    my $vf = shift;
-
-    my $convert_method = 'convert_to_'.lc($config->{convert});
-    my $method_ref   = \&$convert_method;
-
-    my $line = &$method_ref($config, $vf);
-    my $handle = $config->{out_file_handle};
-
-    if(scalar @$line) {
-        print $handle join "\t", @$line;
-        print $handle "\n";
-    }
-}
-
-# converts to Ensembl format
-sub convert_to_ensembl {
-    my $config = shift;
-    my $vf = shift;
-
-    return [
-        $vf->{chr} || $vf->seq_region_name,
-        $vf->start,
-        $vf->end,
-        $vf->allele_string,
-        $vf->strand,
-        $vf->variation_name
-    ];
-}
-
-
-# converts to pileup format
-sub convert_to_pileup {
-    my $config = shift;
-    my $vf = shift;
-
-    # look for imbalance in the allele string
-    my %allele_lengths;
-    my @alleles = split /\//, $vf->allele_string;
-
-    foreach my $allele(@alleles) {
-        $allele =~ s/\-//g;
-        $allele_lengths{length($allele)} = 1;
-    }
-
-    # in/del
-    if(scalar keys %allele_lengths > 1) {
-
-        if($vf->allele_string =~ /\-/) {
-
-            # insertion?
-            if($alleles[0] eq '-') {
-                shift @alleles;
-
-                for my $i(0..$#alleles) {
-                    $alleles[$i] =~ s/\-//g;
-                    $alleles[$i] = '+'.$alleles[$i];
-                }
-            }
-
-            else {
-                @alleles = grep {$_ ne '-'} @alleles;
-
-                for my $i(0..$#alleles) {
-                    $alleles[$i] =~ s/\-//g;
-                    $alleles[$i] = '-'.$alleles[$i];
-                }
-            }
-
-            @alleles = grep {$_ ne '-' && $_ ne '+'} @alleles;
-
-            return [
-                $vf->{chr} || $vf->seq_region_name,
-                $vf->start - 1,
-                '*',
-                (join "/", @alleles),
-            ];
-        }
-
-        else {
-            warn "WARNING: Unable to convert variant to pileup format on line number ", $config->{line_number} unless defined($config->{quiet});
-            return [];
-        }
-
-    }
-
-    # balanced sub
-    else {
-        return [
-            $vf->{chr} || $vf->seq_region_name,
-            $vf->start,
-            shift @alleles,
-            (join "/", @alleles),
-        ];
-    }
-}
-
-# converts to HGVS (hackily returns many lines)
-sub convert_to_hgvs {
-    my $config = shift;
-    my $vf = shift;
-
-    # ensure we have a slice
-    $vf->{slice} ||= get_slice($config, $vf->{chr});
-
-    my $tvs = $vf->get_all_TranscriptVariations;
-
-    my @return = values %{$vf->get_all_hgvs_notations()};
-
-    if(defined($tvs)) {
-        push @return, map {values %{$vf->get_all_hgvs_notations($_->transcript, 'c')}} @$tvs;
-        push @return, map {values %{$vf->get_all_hgvs_notations($_->transcript, 'p')}} @$tvs;
-    }
-
-    return [join "\n", @return];
-}
-
-# prints a line of output from the hash
-sub print_line {
-    my $config = shift;
-    my $line = shift;
-    return unless defined($line);
-
-    my $output;
-
-    # normal
-    if(ref($line) eq 'HASH') {
-        my %extra = %{$line->{Extra}};
-
-        $line->{Extra} = join ';', map { $_.'='.$line->{Extra}->{$_} } keys %{ $line->{Extra} || {} };
-
-        # if the fields have been redefined we need to search through in case
-        # any of the defined fields are actually part of the Extra hash
-        $output = join "\t", map { $line->{$_} || $extra{$_} || '-' } @{$config->{fields}};
-    }
-
-    # gvf
-    else {
-        $output = $line;
-    }
-
-    my $fh = $config->{out_file_handle};
-    print $fh "$output\n";
-}
-
-# outputs usage message
-sub usage {
-    my $usage =<<END;
-#----------------------------------#
-# ENSEMBL VARIANT EFFECT PREDICTOR #
-#----------------------------------#
-
-version $VERSION
-
-By Will McLaren (wm2\@ebi.ac.uk)
-
-http://www.ensembl.org/info/docs/variation/vep/vep_script.html
-
-Usage:
-perl variant_effect_predictor.pl [arguments]
-
-Options
-=======
-
---help                 Display this message and quit
---verbose              Display verbose output as the script runs [default: off]
---quiet                Suppress status and warning messages [default: off]
---no_progress          Suppress progress bars [default: off]
-
---config               Load configuration from file. Any command line options
-                       specified overwrite those in the file [default: off]
-
--i | --input_file      Input file - if not specified, reads from STDIN. Files
-                       may be gzip compressed.
---format               Specify input file format - one of "ensembl", "pileup",
-                       "vcf", "hgvs", "id" or "guess" to try and work out format.
--o | --output_file     Output file. Write to STDOUT by specifying -o STDOUT - this
-                       will force --quiet [default: "variant_effect_output.txt"]
---force_overwrite      Force overwriting of output file [default: quit if file
-                       exists]
---original             Writes output as it was in input - must be used with --filter
-                       [default: off]
---vcf                  Write output as VCF (forces --summary due to limit of one
-                       variant per line, you may also specify --most_severe to print
-                       only most severe consequence per variant) [default: off]
---gvf                  Write output as GVF [default: off]
---fields [field list]  Define a custom output format by specifying a comma-separated
-                       list of field names. Field names normally present in the
-                       "Extra" field may also be specified, including those added by
-                       plugin modules [default: off]
-
---species [species]    Species to use [default: "human"]
-
--t | --terms           Type of consequence terms to output - one of "ensembl", "SO",
-                       "NCBI" [default: ensembl]
-
---sift=[p|s|b]         Add SIFT [p]rediction, [s]core or [b]oth [default: off]
---polyphen=[p|s|b]     Add PolyPhen [p]rediction, [s]core or [b]oth [default: off]
---condel=[p|s|b]       Add Condel SIFT/PolyPhen consensus [p]rediction, [s]core or
-                       [b]oth. Add 1 (i.e. b1) to option to use old Condel algorithm
-                       [default: off]
-
-NB: SIFT, PolyPhen and Condel predictions are currently available for human only
-
---regulatory           Look for overlaps with regulatory regions. The script can
-                       also call if a variant falls in a high information position
-                       within a transcription factor binding site. Output lines have
-                       a Feature type of RegulatoryFeature or MotifFeature
-                       [default: off]
-
-NB: Regulatory consequences are currently available for human and mouse only
-
---custom [file list]   Add custom annotations from tabix-indexed files. See
-                       documentation for full details [default: off]
---plugin [plugin_name] Use named plugin module [default: off]
---hgnc                 Add HGNC gene identifiers to output [default: off]
---hgvs                 Output HGVS identifiers (coding and protein). Requires database
-                       connection [default: off]
---ccds                 Output CCDS transcript identifiers [default: off]
---xref_refseq          Output aligned RefSeq mRNA identifier for transcript. NB: the
-                       RefSeq and Ensembl transcripts aligned in this way MAY NOT, AND
-                       FREQUENCTLY WILL NOT, match exactly in sequence, exon structure
-                       and protein product [default: off]
---protein              Output Ensembl protein identifer [default: off]
---gene                 Force output of Ensembl gene identifer - disabled by default
-                       unless using --cache or --no_whole_genome [default: off]
---canonical            Indicate if the transcript for this consequence is the canonical
-                       transcript for this gene [default: off]
-
---no_intergenic        Excludes intergenic consequences from the output [default: off]
---coding_only          Only return consequences that fall in the coding region of
-                       transcripts [default: off]
---most_severe          Ouptut only the most severe consequence per variation.
-                       Transcript-specific columns will be left blank. [default: off]
---summary              Output only a comma-separated list of all consequences per
-                       variation. Transcript-specific columns will be left blank.
-                       [default: off]
---per_gene             Output only the most severe consequence per gene. Where more
-                       than one transcript has the same consequence, the transcript
-                       chosen is arbitrary. [default: off]
-
-
---check_ref            If specified, checks supplied reference allele against stored
-                       entry in Ensembl Core database [default: off]
---check_existing       If specified, checks for existing co-located variations in the
-                       Ensembl Variation database [default: off]
---failed [0|1]         Include (1) or exclude (0) variants that have been flagged as
-                       failed by Ensembl when checking for existing variants.
-		       [default: exclude]
---check_alleles        If specified, the alleles of existing co-located variations
-                       are compared to the input; an existing variation will only
-                       be reported if no novel allele is in the input (strand is
-                       accounted for) [default: off]
-
---filter [filters]     Filter output by consequence type. Use this to output only
-                       variants that have at least one consequence type matching the
-                       filter. Multiple filters can be used separated by ",". By
-                       combining this with --original it is possible to run the VEP
-                       iteratively to progressively filter a set of variants. See
-                       documentation for full details [default: off]
-
---check_frequency      Turns on frequency filtering. Use this to include or exclude
-                       variants based on the frequency of co-located existing
-                       variants in the Ensembl Variation database. You must also
-                       specify all of the following --freq flags [default: off]
---freq_pop [pop]       Name of the population to use e.g. hapmap_ceu for CEU HapMap,
-                       1kg_yri for YRI 1000 genomes. See documentation for more
-                       details
---freq_freq [freq]     Frequency to use in filter. Must be a number between 0 and 0.5
---freq_gt_lt [gt|lt]   Specify whether the frequency should be greater than (gt) or
-                       less than (lt) --freq_freq
---freq_filter          Specify whether variants that pass the above should be included
-  [exclude|include]    or excluded from analysis
-
---chr [list]           Select a subset of chromosomes to analyse from your file. Any
-                       data not on this chromosome in the input will be skipped. The
-                       list can be comma separated, with "-" characters representing
-                       a range e.g. 1-5,8,15,X [default: off]
---gp                   If specified, tries to read GRCh37 position from GP field in the
-                       INFO column of a VCF file. Only applies when VCF is the input
-                       format and human is the species [default: off]
-
---convert              Convert the input file to the output format specified.
-  [ensembl|vcf|pileup] Converted output is written to the file specified in
-                       --output_file. No consequence calculation is carried out when
-                       doing file conversion. [default: off]
-
---refseq               Use the otherfeatures database to retrieve transcripts - this
-                       database contains RefSeq transcripts (as well as CCDS and
-                       Ensembl EST alignments) [default: off]
---host                 Manually define database host [default: "ensembldb.ensembl.org"]
--u | --user            Database username [default: "anonymous"]
---port                 Database port [default: 5306]
---password             Database password [default: no password]
---genomes              Sets DB connection params for Ensembl Genomes [default: off]
---registry             Registry file to use defines DB connections [default: off]
-                       Defining a registry file overrides above connection settings.
---db_version=[number]  Force script to load DBs from a specific Ensembl version. Not
-                       advised due to likely incompatibilities between API and DB
-
---no_whole_genome      Run in old-style, non-whole genome mode [default: off]
---buffer_size          Sets the number of variants sent in each batch [default: 5000]
-                       Increasing buffer size can retrieve results more quickly
-                       but requires more memory. Only applies to whole genome mode.
-
---cache                Enables read-only use of cache [default: off]
---dir [directory]      Specify the base cache directory to use [default: "\$HOME/.vep/"]
---write_cache          Enable writing to cache [default: off]
---build [all|list]     Build a complete cache for the selected species. Build for all
-                       chromosomes with --build all, or a list of chromosomes (see
-                       --chr). DO NOT USE WHEN CONNECTED TO PUBLIC DB SERVERS AS THIS
-                       VIOLATES OUR FAIR USAGE POLICY [default: off]
-
---compress             Specify utility to decompress cache files - may be "gzcat" or
-                       "gzip -dc" Only use if default does not work [default: zcat]
-
---skip_db_check        ADVANCED! Force the script to use a cache built from a different
-                       database than specified with --host. Only use this if you are
-                       sure the hosts are compatible (e.g. ensembldb.ensembl.org and
-                       useastdb.ensembl.org) [default: off]
---cache_region_size    ADVANCED! The size in base-pairs of the region covered by one
-                       file in the cache. [default: 1MB]
-END
-
-    print $usage;
-}
--- a/variant_effect_predictor/.#variant_effect_predictor.pl.1.23	Fri Aug 03 10:04:48 2012 -0400
+++ /dev/null	Thu Jan 01 00:00:00 1970 +0000
@@ -1,1568 +0,0 @@
-#!/usr/bin/perl
-
-=head1 LICENSE
-
-  Copyright (c) 1999-2012 The European Bioinformatics Institute and
-  Genome Research Limited.  All rights reserved.
-
-  This software is distributed under a modified Apache license.
-  For license details, please see
-
-    http://www.ensembl.org/info/about/code_licence.html
-
-=head1 CONTACT
-
-  Please email comments or questions to the public Ensembl
-  developers list at <dev@ensembl.org>.
-
-  Questions may also be sent to the Ensembl help desk at
-  <helpdesk@ensembl.org>.
-
-=cut
-
-=head1 NAME
-
-Variant Effect Predictor - a script to predict the consequences of genomic variants
-
-http://www.ensembl.org/info/docs/variation/vep/vep_script.html
-
-Version 2.2
-
-by Will McLaren (wm2@ebi.ac.uk)
-=cut
-
-use strict;
-use Getopt::Long;
-use FileHandle;
-use FindBin qw($Bin);
-use lib $Bin;
-
-use Bio::EnsEMBL::Variation::Utils::Sequence qw(unambiguity_code);
-use Bio::EnsEMBL::Variation::Utils::VEP qw(
-    parse_line
-    vf_to_consequences
-    validate_vf
-    convert_to_vcf
-    load_dumped_adaptor_cache
-    dump_adaptor_cache
-    get_all_consequences
-    get_slice
-    build_full_cache
-    read_cache_info
-    get_time
-    debug
-    @OUTPUT_COLS
-    @REG_FEAT_TYPES
-    %FILTER_SHORTCUTS
-);
-
-# global vars
-my $VERSION = '2.4';
-
-# set output autoflush for progress bars
-$| = 1;
-
-# configure from command line opts
-my $config = &configure(scalar @ARGV);
-
-# run the main sub routine
-&main($config);
-
-# this is the main sub-routine - it needs the configured $config hash
-sub main {
-    my $config = shift;
-
-    debug("Starting...") unless defined $config->{quiet};
-
-    my $tr_cache = {};
-    my $rf_cache = {};
-
-    # create a hash to hold slices so we don't get the same one twice
-    my %slice_cache = ();
-
-    my @vfs;
-    my ($vf_count, $total_vf_count);
-    my $in_file_handle = $config->{in_file_handle};
-
-    # initialize line number in config
-    $config->{line_number} = 0;
-
-    # read the file
-    while(<$in_file_handle>) {
-        chomp;
-
-        $config->{line_number}++;
-
-        # header line?
-        if(/^\#/) {
-            if(defined($config->{vcf})) {
-                push @{$config->{headers}}, $_;
-            }
-            next;
-        }
-
-        # configure output file
-        $config->{out_file_handle} ||= &get_out_file_handle($config);
-
-        # some lines (pileup) may actually parse out into more than one variant
-        foreach my $vf(@{&parse_line($config, $_)}) {
-
-            $vf->{_line} = $_ ;#if defined($config->{vcf}) || defined($config->{original});
-
-            # now get the slice
-            if(!defined($vf->{slice})) {
-                my $slice;
-
-                # don't get slices if we're using cache
-                # we can steal them from transcript objects later
-                if((!defined($config->{cache}) && !defined($config->{whole_genome})) || defined($config->{check_ref}) || defined($config->{convert})) {
-
-                    # check if we have fetched this slice already
-                    if(defined $slice_cache{$vf->{chr}}) {
-                        $slice = $slice_cache{$vf->{chr}};
-                    }
-
-                    # if not create a new one
-                    else {
-
-                        $slice = &get_slice($config, $vf->{chr});
-
-                        # if failed, warn and skip this line
-                        if(!defined($slice)) {
-                            warn("WARNING: Could not fetch slice named ".$vf->{chr}." on line ".$config->{line_number}."\n") unless defined $config->{quiet};
-                            next;
-                        }
-
-                        # store the hash
-                        $slice_cache{$vf->{chr}} = $slice;
-                    }
-                }
-
-                $vf->{slice} = $slice;
-            }
-
-            # validate the VF
-            next unless validate_vf($config, $vf);
-
-            # make a name if one doesn't exist
-            $vf->{variation_name} ||= $vf->{chr}.'_'.$vf->{start}.'_'.$vf->{allele_string};
-
-            # jump out to convert here
-            if(defined($config->{convert})) {
-                &convert_vf($config, $vf);
-                next;
-            }
-
-            if(defined $config->{whole_genome}) {
-                push @vfs, $vf;
-                $vf_count++;
-                $total_vf_count++;
-
-                if($vf_count == $config->{buffer_size}) {
-                    debug("Read $vf_count variants into buffer") unless defined($config->{quiet});
-
-                    print_line($config, $_) foreach @{get_all_consequences($config, \@vfs, $tr_cache, $rf_cache)};
-
-                    debug("Processed $total_vf_count total variants") unless defined($config->{quiet});
-
-                    @vfs = ();
-                    $vf_count = 0;
-                }
-            }
-            else {
-                print_line($config, $_) foreach @{vf_to_consequences($config, $vf)};
-                $vf_count++;
-                $total_vf_count++;
-                debug("Processed $vf_count variants") if $vf_count =~ /0$/ && defined($config->{verbose});
-            }
-        }
-    }
-
-    # if in whole-genome mode, finish off the rest of the buffer
-    if(defined $config->{whole_genome} && scalar @vfs) {
-        debug("Read $vf_count variants into buffer") unless defined($config->{quiet});
-
-        print_line($config, $_) foreach @{get_all_consequences($config, \@vfs, $tr_cache, $rf_cache)};
-
-        debug("Processed $total_vf_count total variants") unless defined($config->{quiet});
-
-        debug($config->{filter_count}, "/$total_vf_count variants remain after filtering") if defined($config->{filter}) && !defined($config->{quiet});
-    }
-
-    debug("Executed ", defined($Bio::EnsEMBL::DBSQL::StatementHandle::count_queries) ? $Bio::EnsEMBL::DBSQL::StatementHandle::count_queries : 'unknown number of', " SQL statements") if defined($config->{count_queries}) && !defined($config->{quiet});
-
-    debug("Finished!") unless defined $config->{quiet};
-}
-
-# sets up configuration hash that is used throughout the script
-sub configure {
-    my $args = shift;
-
-    my $config = {};
-
-    GetOptions(
-        $config,
-        'help',                    # displays help message
-
-        # input options,
-        'config=s',                # config file name
-        'input_file|i=s',          # input file name
-        'format=s',                # input file format
-
-        # DB options
-        'species=s',               # species e.g. human, homo_sapiens
-        'registry=s',              # registry file
-        'host=s',                  # database host
-        'port=s',                  # database port
-        'user=s',                  # database user name
-        'password=s',              # database password
-        'db_version=i',            # Ensembl database version to use e.g. 62
-        'genomes',                 # automatically sets DB params for e!Genomes
-        'refseq',                  # use otherfeatures RefSeq DB instead of Ensembl
-        #'no_disconnect',           # disables disconnect_when_inactive
-
-        # runtime options
-        'most_severe',             # only return most severe consequence
-        'summary',                 # only return one line per variation with all consquence types
-        'per_gene',                # only return most severe per gene
-        'buffer_size=i',           # number of variations to read in before analysis
-        'chunk_size=s',            # size in bases of "chunks" used in internal hash structure
-        'failed=i',                # include failed variations when finding existing
-        'no_whole_genome',         # disables now default whole-genome mode
-        'whole_genome',            # proxy for whole genome mode - now just warns user
-        'gp',                      # read coords from GP part of INFO column in VCF (probably only relevant to 1KG)
-        'chr=s',                   # analyse only these chromosomes, e.g. 1-5,10,MT
-        'check_ref',               # check supplied reference allele against DB
-        'check_existing',          # find existing co-located variations
-        'check_alleles',           # only attribute co-located if alleles are the same
-        'check_frequency',         # enable frequency checking
-        'freq_filter=s',           # exclude or include
-        'freq_freq=f',             # frequency to filter on
-        'freq_gt_lt=s',            # gt or lt (greater than or less than)
-        'freq_pop=s',              # population to filter on
-
-        # verbosity options
-        'verbose|v',               # print out a bit more info while running
-        'quiet',                   # print nothing to STDOUT (unless using -o stdout)
-        'no_progress',             # don't display progress bars
-
-        # output options
-        'output_file|o=s',         # output file name
-        'force_overwrite',         # force overwrite of output file if already exists
-        'terms=s',                 # consequence terms to use e.g. NCBI, SO
-        'coding_only',             # only return results for consequences in coding regions
-        'canonical',               # indicates if transcript is canonical
-        'ccds',                    # output CCDS identifer
-        'xref_refseq',             # output refseq mrna xref
-        'protein',                 # add e! protein ID to extra column
-        'hgnc',                    # add HGNC gene ID to extra column
-        'hgvs',                    # add HGVS names to extra column
-        'sift=s',                  # SIFT predictions
-        'polyphen=s',              # PolyPhen predictions
-        'condel=s',                # Condel predictions
-        'gene',                    # force gene column to be populated (disabled by default, enabled when using cache)
-        'regulatory',              # enable regulatory stuff
-        'convert=s',               # convert input to another format (doesn't run VEP)
-        'filter=s',                # run in filtering mode
-        'no_intergenic',           # don't print out INTERGENIC consequences
-        'gvf',                     # produce gvf output
-        'vcf',                     # produce vcf output
-        'original',                # produce output in input format
-        'no_consequences',         # don't calculate consequences
-        'lrg',                     # enable LRG-based features
-        'fields=s',                # define your own output fields
-        'domains',                 # output overlapping protein features
-        'numbers',                 # include exon and intron numbers
-
-        # cache stuff
-        'cache',                   # use cache
-        'write_cache',             # enables writing to the cache
-        'build=s',                 # builds cache from DB from scratch; arg is either all (all top-level seqs) or a list of chrs
-        'no_adaptor_cache',        # don't write adaptor cache
-        'prefetch',                # prefetch exons, translation, introns, codon table etc for each transcript
-        'strip',                   # strips adaptors etc from objects before caching them
-        'rebuild=s',               # rebuilds cache by reading in existing then redumping - probably don't need to use this any more
-        'dir=s',                   # dir where cache is found (defaults to $HOME/.vep/)
-        'cache_region_size=i',     # size of region in bases for each cache file
-        'no_slice_cache',          # tell API not to cache features on slice
-        'standalone',              # standalone renamed offline
-        'offline',                 # offline mode uses minimal set of modules installed in same dir, no DB connection
-        'skip_db_check',           # don't compare DB parameters with cached
-        'compress=s',              # by default we use zcat to decompress; user may want to specify gzcat or "gzip -dc"
-        'custom=s' => ($config->{custom} ||= []), # specify custom tabixed bgzipped file with annotation
-        'tmpdir=s',                # tmp dir used for BigWig retrieval
-        'plugin=s' => ($config->{plugin} ||= []), # specify a method in a module in the plugins directory
-
-        # debug
-        'cluck',                   # these two need some mods to Bio::EnsEMBL::DBSQL::StatementHandle to work. Clucks callback trace and SQL
-        'count_queries',           # counts SQL queries executed
-        'admin',                   # allows me to build off public hosts
-        'debug',                   # print out debug info
-    ) or die "ERROR: Failed to parse command-line flags\n";
-
-    # print usage message if requested or no args supplied
-    if(defined($config->{help}) || !$args) {
-        &usage;
-        exit(0);
-    }
-
-    # dir is where the cache and plugins live
-    $config->{dir} ||= join '/', ($ENV{'HOME'}, '.vep');
-
-    # dir gets set to the specific cache directory later on, so take a copy to use
-    # when configuring plugins
-
-    $config->{toplevel_dir} = $config->{dir};
-
-    # ini file?
-    my $ini_file = $config->{dir}.'/vep.ini';
-
-    if(-e $ini_file) {
-        read_config_from_file($config, $ini_file);
-    }
-
-    # config file?
-    if(defined $config->{config}) {
-        read_config_from_file($config, $config->{config});
-    }
-
-    # can't be both quiet and verbose
-    die "ERROR: Can't be both quiet and verbose!\n" if defined($config->{quiet}) && defined($config->{verbose});
-
-    # check file format
-    if(defined $config->{format}) {
-        die "ERROR: Unrecognised input format specified \"".$config->{format}."\"\n" unless $config->{format} =~ /^(pileup|vcf|guess|hgvs|ensembl|id|vep)$/i;
-    }
-
-    # check convert format
-    if(defined $config->{convert}) {
-        die "ERROR: Unrecognised output format for conversion specified \"".$config->{convert}."\"\n" unless $config->{convert} =~ /vcf|ensembl|pileup|hgvs/i;
-    }
-
-    # check if user still using --standalone
-    if(defined $config->{standalone}) {
-        die "ERROR: --standalone replaced by --offline\n";
-    }
-
-    # connection settings for Ensembl Genomes
-    if($config->{genomes}) {
-        $config->{host} ||= 'mysql.ebi.ac.uk';
-        $config->{port} ||= 4157;
-    }
-
-    # connection settings for main Ensembl
-    else {
-        $config->{species} ||= "homo_sapiens";
-        $config->{host}    ||= 'ensembldb.ensembl.org';
-        $config->{port}    ||= 5306;
-    }
-
-    # refseq or core?
-    if(defined($config->{refseq})) {
-        die "ERROR: SIFT, PolyPhen and Condel predictions not available fore RefSeq transcripts\n" if defined $config->{sift} || defined $config->{polyphen} || defined $config->{condel};
-
-        $config->{core_type} = 'otherfeatures';
-    }
-    else {
-        $config->{core_type} = 'core';
-    }
-
-    # output term
-    if(defined $config->{terms}) {
-        die "ERROR: Unrecognised consequence term type specified \"".$config->{terms}."\" - must be one of ensembl, so, ncbi\n" unless $config->{terms} =~ /ensembl|display|so|ncbi/i;
-        if($config->{terms} =~ /ensembl|display/i) {
-            $config->{terms} = 'display';
-        }
-        else {
-            $config->{terms} = uc($config->{terms});
-        }
-    }
-
-    # check nsSNP tools
-    foreach my $tool(grep {defined $config->{lc($_)}} qw(SIFT PolyPhen Condel)) {
-        die "ERROR: Unrecognised option for $tool \"", $config->{lc($tool)}, "\" - must be one of p (prediction), s (score) or b (both)\n" unless $config->{lc($tool)} =~ /^(s|p|b)/;
-
-        die "ERROR: $tool not available for this species\n" unless $config->{species} =~ /human|homo/i;
-
-        # use V2 of the Condel algorithm, possibly gives fewer false positives
-        if($tool eq 'Condel' && $config->{lc($tool)} =~ /1$/) {
-            $Bio::EnsEMBL::Variation::Utils::Condel::USE_V2 = 0;
-        }
-    }
-
-    # force quiet if outputting to STDOUT
-    if(defined($config->{output_file}) && $config->{output_file} =~ /stdout/i) {
-        delete $config->{verbose} if defined($config->{verbose});
-        $config->{quiet} = 1;
-    }
-
-    # summarise options if verbose
-    if(defined $config->{verbose}) {
-        my $header =<<INTRO;
-#----------------------------------#
-# ENSEMBL VARIANT EFFECT PREDICTOR #
-#----------------------------------#
-
-version $VERSION
-
-By Will McLaren (wm2\@ebi.ac.uk)
-
-Configuration options:
-
-INTRO
-        print $header;
-
-        my $max_length = (sort {$a <=> $b} map {length($_)} keys %$config)[-1];
-
-        foreach my $key(sort keys %$config) {
-            next if ref($config->{$key}) eq 'ARRAY' && scalar @{$config->{$key}} == 0;
-            print $key.(' ' x (($max_length - length($key)) + 4)).(ref($config->{$key}) eq 'ARRAY' ? join "\t", @{$config->{$key}} : $config->{$key})."\n";
-        }
-
-        print "\n".("-" x 20)."\n\n";
-    }
-
-    # check custom annotations
-    for my $i(0..$#{$config->{custom}}) {
-        my $custom = $config->{custom}->[$i];
-
-        my ($filepath, $shortname, $format, $type, $coords) = split /\,/, $custom;
-        $type ||= 'exact';
-        $format ||= 'bed';
-        $coords ||= 0;
-
-        # check type
-        die "ERROR: Type $type for custom annotation file $filepath is not allowed (must be one of \"exact\", \"overlap\")\n" unless $type =~ /exact|overlap/;
-
-        # check format
-        die "ERROR: Format $format for custom annotation file $filepath is not allowed (must be one of \"bed\", \"vcf\", \"gtf\", \"gff\", \"bigwig\")\n" unless $format =~ /bed|vcf|gff|gtf|bigwig/;
-
-        # bigwig format
-        if($format eq 'bigwig') {
-            # check for bigWigToWig
-            die "ERROR: bigWigToWig does not seem to be in your path - this is required to use bigwig format custom annotations\n" unless `which bigWigToWig 2>&1` =~ /bigWigToWig$/;
-        }
-
-        else {
-            # check for tabix
-            die "ERROR: tabix does not seem to be in your path - this is required to use custom annotations\n" unless `which tabix 2>&1` =~ /tabix$/;
-
-            # remote files?
-            if($filepath =~ /tp\:\/\//) {
-                my $remote_test = `tabix $filepath 1:1-1 2>&1`;
-                if($remote_test =~ /fail/) {
-                    die "$remote_test\nERROR: Could not find file or index file for remote annotation file $filepath\n";
-                }
-                elsif($remote_test =~ /get_local_version/) {
-                    debug("Downloaded tabix index file for remote annotation file $filepath") unless defined($config->{quiet});
-                }
-            }
-
-            # check files exist
-            else {
-                die "ERROR: Custom annotation file $filepath not found\n" unless -e $filepath;
-                die "ERROR: Tabix index file $filepath\.tbi not found - perhaps you need to create it first?\n" unless -e $filepath.'.tbi';
-            }
-        }
-
-        $config->{custom}->[$i] = {
-            'file'   => $filepath,
-            'name'   => $shortname || 'CUSTOM'.($i + 1),
-            'type'   => $type,
-            'format' => $format,
-            'coords' => $coords,
-        };
-    }
-
-    # check if using filter and original
-    die "ERROR: You must also provide output filters using --filter to use --original\n" if defined($config->{original}) && !defined($config->{filter});
-
-    # filter by consequence?
-    if(defined($config->{filter})) {
-
-        my %filters = map {$_ => 1} split /\,/, $config->{filter};
-
-        # add in shortcuts
-        foreach my $filter(keys %filters) {
-            my $value = 1;
-            if($filter =~ /^no_/) {
-                delete $filters{$filter};
-                $filter =~ s/^no_//g;
-                $value = 0;
-                $filters{$filter} = $value;
-            }
-
-            if(defined($FILTER_SHORTCUTS{$filter})) {
-                delete $filters{$filter};
-                $filters{$_} = $value for keys %{$FILTER_SHORTCUTS{$filter}};
-            }
-        }
-
-        $config->{filter} = \%filters;
-
-        $config->{filter_count} = 0;
-    }
-
-    # set defaults
-    $config->{user}              ||= 'anonymous';
-    $config->{buffer_size}       ||= 5000;
-    $config->{chunk_size}        ||= '50kb';
-    $config->{output_file}       ||= "variant_effect_output.txt";
-    $config->{tmpdir}            ||= '/tmp';
-    $config->{format}            ||= 'guess';
-    $config->{terms}             ||= 'display';
-    $config->{gene}              ||= 1 unless defined($config->{whole_genome}) && !defined($config->{cache});
-    $config->{cache_region_size} ||= 1000000;
-    $config->{compress}          ||= 'zcat';
-    $config->{tmpdir}            ||= '/tmp';
-
-    # frequency filtering
-    if(defined($config->{check_frequency})) {
-        foreach my $flag(qw(freq_freq freq_filter freq_pop freq_gt_lt)) {
-            die "ERROR: To use --check_frequency you must also specify flag --$flag\n" unless defined $config->{$flag};
-        }
-
-        # need to set check_existing
-        $config->{check_existing} = 1;
-    }
-
-    $config->{check_existing} = 1 if defined $config->{check_alleles};
-
-    # warn users still using whole_genome flag
-    if(defined($config->{whole_genome})) {
-        debug("INFO: Whole-genome mode is now the default run-mode for the script. To disable it, use --no_whole_genome") unless defined($config->{quiet});
-    }
-
-    $config->{whole_genome}      = 1 unless defined $config->{no_whole_genome};
-    $config->{failed}            = 0 unless defined $config->{failed};
-    $config->{chunk_size}        =~ s/mb?/000000/i;
-    $config->{chunk_size}        =~ s/kb?/000/i;
-    $config->{cache_region_size} =~ s/mb?/000000/i;
-    $config->{cache_region_size} =~ s/kb?/000/i;
-
-    # cluck and display executed SQL?
-    $Bio::EnsEMBL::DBSQL::StatementHandle::cluck = 1 if defined($config->{cluck});
-
-    # offline needs cache, can't use HGVS
-    if(defined($config->{offline})) {
-        $config->{cache} = 1;
-
-        die("ERROR: Cannot generate HGVS coordinates in offline mode\n") if defined($config->{hgvs});
-        die("ERROR: Cannot use HGVS as input in offline mode\n") if $config->{format} eq 'hgvs';
-        die("ERROR: Cannot use variant identifiers as input in offline mode\n") if $config->{format} eq 'id';
-        die("ERROR: Cannot do frequency filtering in offline mode\n") if defined($config->{check_frequency});
-    }
-
-    # write_cache needs cache
-    $config->{cache} = 1 if defined $config->{write_cache};
-
-    # no_slice_cache, prefetch and whole_genome have to be on to use cache
-    if(defined($config->{cache})) {
-        $config->{prefetch} = 1;
-        $config->{no_slice_cache} = 1;
-        $config->{whole_genome} = 1;
-        $config->{strip} = 1;
-    }
-
-    $config->{build} = $config->{rebuild} if defined($config->{rebuild});
-
-    # force options for full build
-    if(defined($config->{build})) {
-        $config->{prefetch} = 1;
-        $config->{gene} = 1;
-        $config->{hgnc} = 1;
-        $config->{no_slice_cache} = 1;
-        $config->{cache} = 1;
-        $config->{strip} = 1;
-        $config->{write_cache} = 1;
-    }
-
-    # connect to databases
-    $config->{reg} = &connect_to_dbs($config);
-
-    # complete dir with species name and db_version
-    $config->{dir} .= '/'.(
-        join '/', (
-            defined($config->{offline}) ? $config->{species} : ($config->{reg}->get_alias($config->{species}) || $config->{species}),
-            $config->{db_version} || $config->{reg}->software_version
-        )
-    );
-
-    # warn user cache directory doesn't exist
-    if(!-e $config->{dir}) {
-
-        # if using write_cache
-        if(defined($config->{write_cache})) {
-            debug("INFO: Cache directory ", $config->{dir}, " not found - it will be created") unless defined($config->{quiet});
-        }
-
-        # want to read cache, not found
-        elsif(defined($config->{cache})) {
-            die("ERROR: Cache directory ", $config->{dir}, " not found");
-        }
-    }
-
-    if(defined($config->{cache})) {
-        # read cache info
-        if(read_cache_info($config)) {
-            debug("Read existing cache info") unless defined $config->{quiet};
-        }
-    }
-
-    # we configure plugins here because they can sometimes switch on the
-    # regulatory config option
-    configure_plugins($config);
-
-    # include regulatory modules if requested
-    if(defined($config->{regulatory})) {
-        # do the use statements here so that users don't have to have the
-        # funcgen API installed to use the rest of the script
-        eval q{
-            use Bio::EnsEMBL::Funcgen::DBSQL::RegulatoryFeatureAdaptor;
-            use Bio::EnsEMBL::Funcgen::DBSQL::MotifFeatureAdaptor;
-            use Bio::EnsEMBL::Funcgen::MotifFeature;
-            use Bio::EnsEMBL::Funcgen::RegulatoryFeature;
-            use Bio::EnsEMBL::Funcgen::BindingMatrix;
-        };
-
-        if($@) {
-            die("ERROR: Ensembl Funcgen API must be installed to use --regulatory or plugins that deal with regulatory features\n");
-        }
-    }
-
-    # user defined custom output fields
-    if(defined($config->{fields})) {
-        $config->{fields} = [split ',', $config->{fields}];
-        debug("Output fields redefined (".scalar @{$config->{fields}}." defined)") unless defined($config->{quiet});
-        $config->{fields_redefined} = 1;
-    }
-    $config->{fields} ||= \@OUTPUT_COLS;
-
-    # suppress warnings that the FeatureAdpators spit if using no_slice_cache
-    Bio::EnsEMBL::Utils::Exception::verbose(1999) if defined($config->{no_slice_cache});
-
-    # get adaptors (don't get them in offline mode)
-    unless(defined($config->{offline})) {
-
-        if(defined($config->{cache}) && !defined($config->{write_cache})) {
-
-            # try and load adaptors from cache
-            if(!&load_dumped_adaptor_cache($config)) {
-                &get_adaptors($config);
-                &dump_adaptor_cache($config) if defined($config->{write_cache}) && !defined($config->{no_adaptor_cache});
-            }
-
-            # check cached adaptors match DB params
-            else {
-                my $dbc = $config->{sa}->{dbc};
-
-                my $ok = 1;
-
-                if($dbc->{_host} ne $config->{host}) {
-
-                    # ens-livemirror, useastdb and ensembldb should all have identical DBs
-                    unless(
-                        (
-                            $dbc->{_host} eq 'ens-livemirror'
-                            || $dbc->{_host} eq 'ensembldb.ensembl.org'
-                            || $dbc->{_host} eq 'useastdb.ensembl.org'
-                        ) && (
-                            $config->{host} eq 'ens-livemirror'
-                            || $config->{host} eq 'ensembldb.ensembl.org'
-                            || $config->{host} eq 'useastdb.ensembl.org'
-                        )
-                    ) {
-                        $ok = 0;
-                    }
-
-                    unless(defined($config->{skip_db_check})) {
-                        # but we still need to reconnect
-                        debug("INFO: Defined host ", $config->{host}, " is different from cached ", $dbc->{_host}, " - reconnecting to host") unless defined($config->{quiet});
-
-                        &get_adaptors($config);
-                    }
-                }
-
-                if(!$ok) {
-                    if(defined($config->{skip_db_check})) {
-                        debug("INFO: Defined host ", $config->{host}, " is different from cached ", $dbc->{_host}) unless defined($config->{quiet});
-                    }
-                    else {
-                        die "ERROR: Defined host ", $config->{host}, " is different from cached ", $dbc->{_host}, ". If you are sure this is OK, rerun with -skip_db_check flag set";
-                    }
-                }
-            }
-        }
-        else {
-            &get_adaptors($config);
-            &dump_adaptor_cache($config) if defined($config->{write_cache}) && !defined($config->{no_adaptor_cache});
-        }
-
-        # reg adaptors (only fetches if not retrieved from cache already)
-        &get_reg_adaptors($config) if defined($config->{regulatory});
-    }
-
-    # get terminal width for progress bars
-    unless(defined($config->{quiet})) {
-        my $width;
-
-        # module may not be installed
-        eval q{
-            use Term::ReadKey;
-        };
-
-        if(!$@) {
-            my ($w, $h);
-
-            # module may be installed, but e.g.
-            eval {
-                ($w, $h) = GetTerminalSize();
-            };
-
-            $width = $w if defined $w;
-        }
-
-        $width ||= 60;
-        $width -= 12;
-        $config->{terminal_width} = $width;
-    }
-
-    # jump out to build cache if requested
-    if(defined($config->{build})) {
-
-        if($config->{host} =~ /^(ensembl|useast)db\.ensembl\.org$/ && !defined($config->{admin})) {
-            die("ERROR: Cannot build cache using public database server ", $config->{host}, "\n");
-        }
-
-        # build the cache
-        debug("Building cache for ".$config->{species}) unless defined($config->{quiet});
-        build_full_cache($config);
-
-        # exit script
-        debug("Finished building cache") unless defined($config->{quiet});
-        exit(0);
-    }
-
-
-    # warn user DB will be used for SIFT/PolyPhen/Condel/HGVS/frequency/LRG
-    if(defined($config->{cache})) {
-
-        # these two def depend on DB
-        foreach my $param(grep {defined $config->{$_}} qw(hgvs check_frequency lrg)) {
-            debug("INFO: Database will be accessed when using --$param") unless defined($config->{quiet});
-        }
-
-        # as does using HGVS or IDs as input
-        debug("INFO: Database will be accessed when using --format ", $config->{format}) if ($config->{format} eq 'id' || $config->{format} eq 'hgvs') && !defined($config->{quiet});
-
-        # the rest may be in the cache
-        foreach my $param(grep {defined $config->{$_}} qw(sift polyphen condel regulatory)) {
-            next if defined($config->{'cache_'.$param});
-            debug("INFO: Database will be accessed when using --$param; consider using the complete cache containing $param data (see documentation for details)") unless defined($config->{quiet});
-        }
-    }
-
-    # get list of chrs if supplied
-    if(defined($config->{chr})) {
-        my %chrs;
-
-        foreach my $val(split /\,/, $config->{chr}) {
-            my @nnn = split /\-/, $val;
-
-            foreach my $chr($nnn[0]..$nnn[-1]) {
-                $chrs{$chr} = 1;
-            }
-        }
-
-        $config->{chr} = \%chrs;
-    }
-
-    # get input file handle
-    $config->{in_file_handle} = &get_in_file_handle($config);
-
-    return $config;
-}
-
-# reads config from a file
-sub read_config_from_file {
-    my $config = shift;
-    my $file = shift;
-
-    open CONFIG, $file or die "ERROR: Could not open config file \"$file\"\n";
-
-    debug("Reading configuration from $file") unless defined($config->{quiet});
-
-    while(<CONFIG>) {
-        next if /^\#/;
-        my @split = split /\s+|\=/;
-        my $key = shift @split;
-        $key =~ s/^\-//g;
-
-        if(defined($config->{$key}) && ref($config->{$key}) eq 'ARRAY') {
-            push @{$config->{$key}}, @split;
-        }
-        else {
-            $config->{$key} ||= $split[0];
-        }
-    }
-
-    close CONFIG;
-}
-
-# configures custom VEP plugins
-sub configure_plugins {
-
-    my $config = shift;
-
-    $config->{plugins} = [];
-
-    if (my @plugins = @{ $config->{plugin} }) {
-
-        # add the Plugins directory onto @INC
-
-        unshift @INC, $config->{toplevel_dir}."/Plugins";
-
-        for my $plugin (@plugins) {
-
-            # parse out the module name and parameters
-
-            my ($module, @params) = split /,/, $plugin;
-
-            # check we can use the module
-
-            eval qq{
-                use $module;
-            };
-            if ($@) {
-                debug("Failed to compile plugin $module: $@");
-                next;
-            }
-
-            # now check we can instantiate it, passing any parameters to the constructor
-
-            my $instance;
-
-            eval {
-                $instance = $module->new($config, @params);
-            };
-            if ($@) {
-                debug("Failed to instantiate plugin $module: $@");
-                next;
-            }
-
-            # check that the versions match
-
-            my $plugin_version;
-
-            if ($instance->can('version')) {
-                $plugin_version = $instance->version;
-            }
-
-            my $version_ok = 1;
-
-            if ($plugin_version) {
-                my ($plugin_major, $plugin_minor, $plugin_maintenance) = split /\./, $plugin_version;
-                my ($major, $minor, $maintenance) = split /\./, $VERSION;
-
-                if ($plugin_major != $major) {
-                    debug("Warning: plugin $plugin version ($plugin_version) does not match the current VEP version ($VERSION)");
-                    $version_ok = 0;
-                }
-            }
-            else {
-                debug("Warning: plugin $plugin does not define a version number");
-                $version_ok = 0;
-            }
-
-            debug("You may experience unexpected behaviour with this plugin") unless $version_ok;
-
-            # check that it implements all necessary methods
-
-            for my $required(qw(run get_header_info check_feature_type check_variant_feature_type)) {
-                unless ($instance->can($required)) {
-                    debug("Plugin $module doesn't implement a required method '$required', does it inherit from BaseVepPlugin?");
-                    next;
-                }
-            }
-
-            # all's good, so save the instance in our list of plugins
-
-            push @{ $config->{plugins} }, $instance;
-
-            debug("Loaded plugin: $module");
-
-            # for convenience, check if the plugin wants regulatory stuff and turn on the config option if so
-
-            if (grep { $_ =~ /motif|regulatory/i } @{ $instance->feature_types }) {
-                debug("Fetching regulatory features for plugin: $module");
-                $config->{regulatory} = 1;
-            }
-        }
-    }
-}
-
-# connects to DBs (not done in offline mode)
-sub connect_to_dbs {
-    my $config = shift;
-
-    # get registry
-    my $reg = 'Bio::EnsEMBL::Registry';
-
-    unless(defined($config->{offline})) {
-        # load DB options from registry file if given
-        if(defined($config->{registry})) {
-            debug("Loading DB config from registry file ", $config->{registry}) unless defined($config->{quiet});
-            $reg->load_all(
-                $config->{registry},
-                $config->{verbose},
-                undef,
-                $config->{no_slice_cache}
-            );
-        }
-
-        # otherwise manually connect to DB server
-        else {
-            $reg->load_registry_from_db(
-                -host       => $config->{host},
-                -user       => $config->{user},
-                -pass       => $config->{password},
-                -port       => $config->{port},
-                -db_version => $config->{db_version},
-                -species    => $config->{species} =~ /^[a-z]+\_[a-z]+/i ? $config->{species} : undef,
-                -verbose    => $config->{verbose},
-                -no_cache   => $config->{no_slice_cache},
-            );
-        }
-
-        eval { $reg->set_reconnect_when_lost() };
-
-        if(defined($config->{verbose})) {
-            # get a meta container adaptors to check version
-            my $core_mca = $reg->get_adaptor($config->{species}, 'core', 'metacontainer');
-            my $var_mca = $reg->get_adaptor($config->{species}, 'variation', 'metacontainer');
-
-            if($core_mca && $var_mca) {
-                debug(
-                    "Connected to core version ", $core_mca->get_schema_version, " database ",
-                    "and variation version ", $var_mca->get_schema_version, " database"
-                );
-            }
-        }
-    }
-
-    return $reg;
-}
-
-# get adaptors from DB
-sub get_adaptors {
-    my $config = shift;
-
-    die "ERROR: No registry" unless defined $config->{reg};
-
-    $config->{vfa}   = $config->{reg}->get_adaptor($config->{species}, 'variation', 'variationfeature');
-    $config->{svfa}  = $config->{reg}->get_adaptor($config->{species}, 'variation', 'structuralvariationfeature');
-    $config->{tva}   = $config->{reg}->get_adaptor($config->{species}, 'variation', 'transcriptvariation');
-    $config->{pfpma} = $config->{reg}->get_adaptor($config->{species}, 'variation', 'proteinfunctionpredictionmatrix');
-    $config->{va}    = $config->{reg}->get_adaptor($config->{species}, 'variation', 'variation');
-
-    # get fake ones for species with no var DB
-    if(!defined($config->{vfa})) {
-        $config->{vfa}  = Bio::EnsEMBL::Variation::DBSQL::VariationFeatureAdaptor->new_fake($config->{species});
-        $config->{svfa} = Bio::EnsEMBL::Variation::DBSQL::StructuralVariationFeatureAdaptor->new_fake($config->{species});
-        $config->{tva}  = Bio::EnsEMBL::Variation::DBSQL::TranscriptVariationAdaptor->new_fake($config->{species});
-    }
-
-    $config->{sa}  = $config->{reg}->get_adaptor($config->{species}, $config->{core_type}, 'slice');
-    $config->{ga}  = $config->{reg}->get_adaptor($config->{species}, $config->{core_type}, 'gene');
-    $config->{ta}  = $config->{reg}->get_adaptor($config->{species}, $config->{core_type}, 'transcript');
-    $config->{mca} = $config->{reg}->get_adaptor($config->{species}, $config->{core_type}, 'metacontainer');
-    $config->{csa} = $config->{reg}->get_adaptor($config->{species}, $config->{core_type}, 'coordsystem');
-
-    # cache schema version
-    $config->{mca}->get_schema_version if defined $config->{mca};
-
-    # check we got slice adaptor - can't continue without a core DB
-    die("ERROR: Could not connect to core database\n") unless defined $config->{sa};
-}
-
-# gets regulatory adaptors
-sub get_reg_adaptors {
-    my $config = shift;
-
-    foreach my $type(@REG_FEAT_TYPES) {
-        next if defined($config->{$type.'_adaptor'});
-
-        my $adaptor = $config->{reg}->get_adaptor($config->{species}, 'funcgen', $type);
-        if(defined($adaptor)) {
-            $config->{$type.'_adaptor'} = $adaptor;
-        }
-        else {
-            delete $config->{regulatory};
-            last;
-        }
-    }
-}
-
-# gets file handle for input
-sub get_in_file_handle {
-    my $config = shift;
-
-    # define the filehandle to read input from
-    my $in_file_handle = new FileHandle;
-
-    if(defined($config->{input_file})) {
-
-        # check defined input file exists
-        die("ERROR: Could not find input file ", $config->{input_file}, "\n") unless -e $config->{input_file};
-
-        if($config->{input_file} =~ /\.gz$/){
-            $in_file_handle->open($config->{compress}." ". $config->{input_file} . " | " ) or die("ERROR: Could not read from input file ", $config->{input_file}, "\n");
-        }
-        else {
-            $in_file_handle->open( $config->{input_file} ) or die("ERROR: Could not read from input file ", $config->{input_file}, "\n");
-        }
-    }
-
-    # no file specified - try to read data off command line
-    else {
-        $in_file_handle = 'STDIN';
-        debug("Reading input from STDIN (or maybe you forgot to specify an input file?)...") unless defined $config->{quiet};
-    }
-
-    return $in_file_handle;
-}
-
-# gets file handle for output and adds header
-sub get_out_file_handle {
-    my $config = shift;
-
-    # define filehandle to write to
-    my $out_file_handle = new FileHandle;
-
-    # check if file exists
-    if(-e $config->{output_file} && !defined($config->{force_overwrite})) {
-        die("ERROR: Output file ", $config->{output_file}, " already exists. Specify a different output file with --output_file or overwrite existing file with --force_overwrite\n");
-    }
-
-    if($config->{output_file} =~ /stdout/i) {
-        $out_file_handle = *STDOUT;
-    }
-    else {
-        $out_file_handle->open(">".$config->{output_file}) or die("ERROR: Could not write to output file ", $config->{output_file}, "\n");
-    }
-
-    # define headers for a VCF file
-    my @vcf_headers = (
-        '#CHROM',
-        'POS',
-        'ID',
-        'REF',
-        'ALT',
-        'QUAL',
-        'FILTER',
-        'INFO'
-    );
-
-    # file conversion, don't want to add normal headers
-    if(defined($config->{convert})) {
-        # header for VCF
-        if($config->{convert} =~ /vcf/i) {
-            print $out_file_handle "##fileformat=VCFv4.0\n";
-            print $out_file_handle join "\t", @vcf_headers;
-            print $out_file_handle "\n";
-        }
-
-        return $out_file_handle;
-    }
-
-    # GVF output, no header
-    elsif(defined($config->{gvf}) || defined($config->{original})) {
-        print $out_file_handle join "\n", @{$config->{headers}} if defined($config->{headers}) && defined($config->{original});
-        return $out_file_handle;
-    }
-
-    elsif(defined($config->{vcf})) {
-
-        # create an info string for the VCF header
-
-        # define headers that would normally go in the extra field
-        # keyed on the config parameter used to turn it on
-        # should probably move this elsewhere to avoid things getting missed out
-        my %extra_headers = (
-            protein    => ['ENSP'],
-            canonical  => ['CANONICAL'],
-            ccds       => ['CCDS'],
-            hgvs       => ['HGVSc','HGVSp'],
-            sift       => ['SIFT'],
-            polyphen   => ['PolyPhen'],
-            condel     => ['Condel'],
-            numbers    => ['EXON','INTRON'],
-            domains    => ['domains'],
-            regulatory => ['MATRIX','MATRIX_POS','HIGH_INF_POS','MOTIF_SCORE_CHANGE'],
-        );
-
-        my @new_headers;
-
-        # if the user has defined the fields themselves, we don't need to worry
-        if(defined $config->{fields_redefined}) {
-            @new_headers = @{$config->{fields}};
-        }
-        else {
-            @new_headers = (
-
-                # get default headers, minus variation name and location (already encoded in VCF)
-                grep {
-                    $_ ne 'Uploaded_variation' and
-                    $_ ne 'Location' and
-                    $_ ne 'Extra'
-                } @{$config->{fields}},
-
-                # get extra headers
-                map {@{$extra_headers{$_}}}
-                grep {defined $config->{$_}}
-                keys %extra_headers
-            );
-
-            # plugin headers
-            foreach my $plugin_header(split /\n/, get_plugin_headers($config)) {
-                $plugin_header =~ /\#\# (.+?)\t\:.+/;
-                push @new_headers, $1;
-            }
-
-            # redefine the main headers list in config
-            $config->{fields} = \@new_headers;
-        }
-
-        # add the newly defined headers as a header to the VCF
-        my $string = join '|', @{$config->{fields}};
-        my @vcf_info_strings = ('##INFO=<ID=CSQ,Number=.,Type=String,Description="Consequence type as predicted by VEP. Format: '.$string.'">');
-
-        # add custom headers
-        foreach my $custom(@{$config->{custom}}) {
-            push @vcf_info_strings, '##INFO=<ID='.$custom->{name}.',Number=.,Type=String,Description="'.$custom->{file}.' ('.$custom->{type}.')">';
-        }
-
-        # if this is already a VCF file, we need to add our new headers in the right place
-        if(defined($config->{headers})) {
-
-            for my $i(0..$#{$config->{headers}}) {
-                if($config->{headers}->[$i] =~ /^\#CHROM\s+POS\s+ID/) {
-                    splice(@{$config->{headers}}, $i, 0, @vcf_info_strings);
-                }
-            }
-
-            print $out_file_handle join "\n", @{$config->{headers}};
-            print $out_file_handle "\n";
-        }
-
-        else {
-            print $out_file_handle "##fileformat=VCFv4.0\n";
-            print $out_file_handle join "\n", @vcf_info_strings;
-            print $out_file_handle "\n";
-            print $out_file_handle join "\t", @vcf_headers;
-            print $out_file_handle "\n";
-        }
-
-        return $out_file_handle;
-    }
-
-    # make header
-    my $time = &get_time;
-    my $db_string = $config->{mca}->dbc->dbname." on ".$config->{mca}->dbc->host if defined $config->{mca};
-    $db_string .= "\n## Using cache in ".$config->{dir} if defined($config->{cache});
-    my $version_string =
-        "Using API version ".$config->{reg}->software_version.
-        ", DB version ".(defined $config->{mca} && $config->{mca}->get_schema_version ? $config->{mca}->get_schema_version : '?');
-
-    my $header =<<HEAD;
-## ENSEMBL VARIANT EFFECT PREDICTOR v$VERSION
-## Output produced at $time
-## Connected to $db_string
-## $version_string
-## Extra column keys:
-## CANONICAL    : Indicates if transcript is canonical for this gene
-## CCDS         : Indicates if transcript is a CCDS transcript
-## HGNC         : HGNC gene identifier
-## ENSP         : Ensembl protein identifer
-## HGVSc        : HGVS coding sequence name
-## HGVSp        : HGVS protein sequence name
-## SIFT         : SIFT prediction
-## PolyPhen     : PolyPhen prediction
-## Condel       : Condel SIFT/PolyPhen consensus prediction
-## EXON         : Exon number
-## INTRON       : Intron number
-## DOMAINS      : The source and identifer of any overlapping protein domains
-## MATRIX       : The source and identifier of a transcription factor binding profile (TFBP) aligned at this position
-## MATRIX_POS   : The relative position of the variation in the aligned TFBP
-## HIGH_INF_POS : A flag indicating if the variant falls in a high information position of the TFBP
-## MOTIF_SCORE_CHANGE : The difference in motif score of the reference and variant sequences for the TFBP
-HEAD
-
-    $header .= get_plugin_headers($config);
-
-    # add headers
-    print $out_file_handle $header;
-
-    # add custom data defs
-    if(defined($config->{custom})) {
-        foreach my $custom(@{$config->{custom}}) {
-            print $out_file_handle '## '.$custom->{name}."\t: ".$custom->{file}.' ('.$custom->{type}.")\n";
-        }
-    }
-
-    # add column headers
-    print $out_file_handle '#', (join "\t", @{$config->{fields}});
-    print $out_file_handle "\n";
-
-    return $out_file_handle;
-}
-
-sub get_plugin_headers {
-
-    my $config = shift;
-
-    my $header = "";
-
-    for my $plugin (@{ $config->{plugins} }) {
-        if (my $hdr = $plugin->get_header_info) {
-            for my $key (keys %$hdr) {
-                my $val = $hdr->{$key};
-
-                $header .= "## $key\t: $val\n";
-            }
-        }
-    }
-
-    return $header;
-}
-
-# convert a variation feature to a line of output
-sub convert_vf {
-    my $config = shift;
-    my $vf = shift;
-
-    my $convert_method = 'convert_to_'.lc($config->{convert});
-    my $method_ref   = \&$convert_method;
-
-    my $line = &$method_ref($config, $vf);
-    my $handle = $config->{out_file_handle};
-
-    if(scalar @$line) {
-        print $handle join "\t", @$line;
-        print $handle "\n";
-    }
-}
-
-# converts to Ensembl format
-sub convert_to_ensembl {
-    my $config = shift;
-    my $vf = shift;
-
-    return [
-        $vf->{chr} || $vf->seq_region_name,
-        $vf->start,
-        $vf->end,
-        $vf->allele_string,
-        $vf->strand,
-        $vf->variation_name
-    ];
-}
-
-
-# converts to pileup format
-sub convert_to_pileup {
-    my $config = shift;
-    my $vf = shift;
-
-    # look for imbalance in the allele string
-    my %allele_lengths;
-    my @alleles = split /\//, $vf->allele_string;
-
-    foreach my $allele(@alleles) {
-        $allele =~ s/\-//g;
-        $allele_lengths{length($allele)} = 1;
-    }
-
-    # in/del
-    if(scalar keys %allele_lengths > 1) {
-
-        if($vf->allele_string =~ /\-/) {
-
-            # insertion?
-            if($alleles[0] eq '-') {
-                shift @alleles;
-
-                for my $i(0..$#alleles) {
-                    $alleles[$i] =~ s/\-//g;
-                    $alleles[$i] = '+'.$alleles[$i];
-                }
-            }
-
-            else {
-                @alleles = grep {$_ ne '-'} @alleles;
-
-                for my $i(0..$#alleles) {
-                    $alleles[$i] =~ s/\-//g;
-                    $alleles[$i] = '-'.$alleles[$i];
-                }
-            }
-
-            @alleles = grep {$_ ne '-' && $_ ne '+'} @alleles;
-
-            return [
-                $vf->{chr} || $vf->seq_region_name,
-                $vf->start - 1,
-                '*',
-                (join "/", @alleles),
-            ];
-        }
-
-        else {
-            warn "WARNING: Unable to convert variant to pileup format on line number ", $config->{line_number} unless defined($config->{quiet});
-            return [];
-        }
-
-    }
-
-    # balanced sub
-    else {
-        return [
-            $vf->{chr} || $vf->seq_region_name,
-            $vf->start,
-            shift @alleles,
-            (join "/", @alleles),
-        ];
-    }
-}
-
-# converts to HGVS (hackily returns many lines)
-sub convert_to_hgvs {
-    my $config = shift;
-    my $vf = shift;
-
-    # ensure we have a slice
-    $vf->{slice} ||= get_slice($config, $vf->{chr});
-
-    my $tvs = $vf->get_all_TranscriptVariations;
-
-    my @return = values %{$vf->get_all_hgvs_notations()};
-
-    if(defined($tvs)) {
-        push @return, map {values %{$vf->get_all_hgvs_notations($_->transcript, 'c')}} @$tvs;
-        push @return, map {values %{$vf->get_all_hgvs_notations($_->transcript, 'p')}} @$tvs;
-    }
-
-    return [join "\n", @return];
-}
-
-# prints a line of output from the hash
-sub print_line {
-    my $config = shift;
-    my $line = shift;
-    return unless defined($line);
-
-    my $output;
-
-    # normal
-    if(ref($line) eq 'HASH') {
-        my %extra = %{$line->{Extra}};
-
-        $line->{Extra} = join ';', map { $_.'='.$line->{Extra}->{$_} } keys %{ $line->{Extra} || {} };
-
-        # if the fields have been redefined we need to search through in case
-        # any of the defined fields are actually part of the Extra hash
-        $output = join "\t", map { $line->{$_} || $extra{$_} || '-' } @{$config->{fields}};
-    }
-
-    # gvf
-    else {
-        $output = $line;
-    }
-
-    my $fh = $config->{out_file_handle};
-    print $fh "$output\n";
-}
-
-# outputs usage message
-sub usage {
-    my $usage =<<END;
-#----------------------------------#
-# ENSEMBL VARIANT EFFECT PREDICTOR #
-#----------------------------------#
-
-version $VERSION
-
-By Will McLaren (wm2\@ebi.ac.uk)
-
-http://www.ensembl.org/info/docs/variation/vep/vep_script.html
-
-Usage:
-perl variant_effect_predictor.pl [arguments]
-
-Options
-=======
-
---help                 Display this message and quit
---verbose              Display verbose output as the script runs [default: off]
---quiet                Suppress status and warning messages [default: off]
---no_progress          Suppress progress bars [default: off]
-
---config               Load configuration from file. Any command line options
-                       specified overwrite those in the file [default: off]
-
--i | --input_file      Input file - if not specified, reads from STDIN. Files
-                       may be gzip compressed.
---format               Specify input file format - one of "ensembl", "pileup",
-                       "vcf", "hgvs", "id" or "guess" to try and work out format.
--o | --output_file     Output file. Write to STDOUT by specifying -o STDOUT - this
-                       will force --quiet [default: "variant_effect_output.txt"]
---force_overwrite      Force overwriting of output file [default: quit if file
-                       exists]
---original             Writes output as it was in input - must be used with --filter
-                       [default: off]
---vcf                  Write output as VCF (forces --summary due to limit of one
-                       variant per line, you may also specify --most_severe to print
-                       only most severe consequence per variant) [default: off]
---gvf                  Write output as GVF [default: off]
---fields [field list]  Define a custom output format by specifying a comma-separated
-                       list of field names. Field names normally present in the
-                       "Extra" field may also be specified, including those added by
-                       plugin modules [default: off]
-
---species [species]    Species to use [default: "human"]
-
--t | --terms           Type of consequence terms to output - one of "ensembl", "SO",
-                       "NCBI" [default: ensembl]
-
---sift=[p|s|b]         Add SIFT [p]rediction, [s]core or [b]oth [default: off]
---polyphen=[p|s|b]     Add PolyPhen [p]rediction, [s]core or [b]oth [default: off]
---condel=[p|s|b]       Add Condel SIFT/PolyPhen consensus [p]rediction, [s]core or
-                       [b]oth. Add 1 (i.e. b1) to option to use old Condel algorithm
-                       [default: off]
-
-NB: SIFT, PolyPhen and Condel predictions are currently available for human only
-
---regulatory           Look for overlaps with regulatory regions. The script can
-                       also call if a variant falls in a high information position
-                       within a transcription factor binding site. Output lines have
-                       a Feature type of RegulatoryFeature or MotifFeature
-                       [default: off]
-
-NB: Regulatory consequences are currently available for human and mouse only
-
---custom [file list]   Add custom annotations from tabix-indexed files. See
-                       documentation for full details [default: off]
---plugin [plugin_name] Use named plugin module [default: off]
---hgnc                 Add HGNC gene identifiers to output [default: off]
---hgvs                 Output HGVS identifiers (coding and protein). Requires database
-                       connection [default: off]
---ccds                 Output CCDS transcript identifiers [default: off]
---xref_refseq          Output aligned RefSeq mRNA identifier for transcript. NB: the
-                       RefSeq and Ensembl transcripts aligned in this way MAY NOT, AND
-                       FREQUENCTLY WILL NOT, match exactly in sequence, exon structure
-                       and protein product [default: off]
---protein              Output Ensembl protein identifer [default: off]
---gene                 Force output of Ensembl gene identifer - disabled by default
-                       unless using --cache or --no_whole_genome [default: off]
---canonical            Indicate if the transcript for this consequence is the canonical
-                       transcript for this gene [default: off]
---domains              Include details of any overlapping protein domains [default: off]
---numbers              Include exon & intron numbers [default: off]
-
---no_intergenic        Excludes intergenic consequences from the output [default: off]
---coding_only          Only return consequences that fall in the coding region of
-                       transcripts [default: off]
---most_severe          Ouptut only the most severe consequence per variation.
-                       Transcript-specific columns will be left blank. [default: off]
---summary              Output only a comma-separated list of all consequences per
-                       variation. Transcript-specific columns will be left blank.
-                       [default: off]
---per_gene             Output only the most severe consequence per gene. Where more
-                       than one transcript has the same consequence, the transcript
-                       chosen is arbitrary. [default: off]
-
-
---check_ref            If specified, checks supplied reference allele against stored
-                       entry in Ensembl Core database [default: off]
---check_existing       If specified, checks for existing co-located variations in the
-                       Ensembl Variation database [default: off]
---failed [0|1]         Include (1) or exclude (0) variants that have been flagged as
-                       failed by Ensembl when checking for existing variants.
-		       [default: exclude]
---check_alleles        If specified, the alleles of existing co-located variations
-                       are compared to the input; an existing variation will only
-                       be reported if no novel allele is in the input (strand is
-                       accounted for) [default: off]
-
---filter [filters]     Filter output by consequence type. Use this to output only
-                       variants that have at least one consequence type matching the
-                       filter. Multiple filters can be used separated by ",". By
-                       combining this with --original it is possible to run the VEP
-                       iteratively to progressively filter a set of variants. See
-                       documentation for full details [default: off]
-
---check_frequency      Turns on frequency filtering. Use this to include or exclude
-                       variants based on the frequency of co-located existing
-                       variants in the Ensembl Variation database. You must also
-                       specify all of the following --freq flags [default: off]
---freq_pop [pop]       Name of the population to use e.g. hapmap_ceu for CEU HapMap,
-                       1kg_yri for YRI 1000 genomes. See documentation for more
-                       details
---freq_freq [freq]     Frequency to use in filter. Must be a number between 0 and 0.5
---freq_gt_lt [gt|lt]   Specify whether the frequency should be greater than (gt) or
-                       less than (lt) --freq_freq
---freq_filter          Specify whether variants that pass the above should be included
-  [exclude|include]    or excluded from analysis
-
---chr [list]           Select a subset of chromosomes to analyse from your file. Any
-                       data not on this chromosome in the input will be skipped. The
-                       list can be comma separated, with "-" characters representing
-                       a range e.g. 1-5,8,15,X [default: off]
---gp                   If specified, tries to read GRCh37 position from GP field in the
-                       INFO column of a VCF file. Only applies when VCF is the input
-                       format and human is the species [default: off]
-
---convert              Convert the input file to the output format specified.
-  [ensembl|vcf|pileup] Converted output is written to the file specified in
-                       --output_file. No consequence calculation is carried out when
-                       doing file conversion. [default: off]
-
---refseq               Use the otherfeatures database to retrieve transcripts - this
-                       database contains RefSeq transcripts (as well as CCDS and
-                       Ensembl EST alignments) [default: off]
---host                 Manually define database host [default: "ensembldb.ensembl.org"]
--u | --user            Database username [default: "anonymous"]
---port                 Database port [default: 5306]
---password             Database password [default: no password]
---genomes              Sets DB connection params for Ensembl Genomes [default: off]
---registry             Registry file to use defines DB connections [default: off]
-                       Defining a registry file overrides above connection settings.
---db_version=[number]  Force script to load DBs from a specific Ensembl version. Not
-                       advised due to likely incompatibilities between API and DB
-
---no_whole_genome      Run in old-style, non-whole genome mode [default: off]
---buffer_size          Sets the number of variants sent in each batch [default: 5000]
-                       Increasing buffer size can retrieve results more quickly
-                       but requires more memory. Only applies to whole genome mode.
-
---cache                Enables read-only use of cache [default: off]
---dir [directory]      Specify the base cache directory to use [default: "\$HOME/.vep/"]
---write_cache          Enable writing to cache [default: off]
---build [all|list]     Build a complete cache for the selected species. Build for all
-                       chromosomes with --build all, or a list of chromosomes (see
-                       --chr). DO NOT USE WHEN CONNECTED TO PUBLIC DB SERVERS AS THIS
-                       VIOLATES OUR FAIR USAGE POLICY [default: off]
-
---compress             Specify utility to decompress cache files - may be "gzcat" or
-                       "gzip -dc" Only use if default does not work [default: zcat]
-
---skip_db_check        ADVANCED! Force the script to use a cache built from a different
-                       database than specified with --host. Only use this if you are
-                       sure the hosts are compatible (e.g. ensembldb.ensembl.org and
-                       useastdb.ensembl.org) [default: off]
---cache_region_size    ADVANCED! The size in base-pairs of the region covered by one
-                       file in the cache. [default: 1MB]
-END
-
-    print $usage;
-}
--- a/variant_effect_predictor/.#variant_effect_predictor.pl.1.3	Fri Aug 03 10:04:48 2012 -0400
+++ /dev/null	Thu Jan 01 00:00:00 1970 +0000
@@ -1,1192 +0,0 @@
-#!/usr/bin/perl
-
-=head1 LICENSE
-
-  Copyright (c) 1999-2011 The European Bioinformatics Institute and
-  Genome Research Limited.  All rights reserved.
-
-  This software is distributed under a modified Apache license.
-  For license details, please see
-
-    http://www.ensembl.org/info/about/code_licence.html
-
-=head1 CONTACT
-
-  Please email comments or questions to the public Ensembl
-  developers list at <dev@ensembl.org>.
-
-  Questions may also be sent to the Ensembl help desk at
-  <helpdesk@ensembl.org>.
-
-=cut
-
-=head1 NAME
-
-Variant Effect Predictor - a script to predict the consequences of genomic variants
-
-http://www.ensembl.org/info/docs/variation/vep/vep_script.html
-
-Version 2.2
-
-by Will McLaren (wm2@ebi.ac.uk)
-=cut
-
-use strict;
-use Getopt::Long;
-use FileHandle;
-use Bio::EnsEMBL::Variation::Utils::Sequence qw(unambiguity_code);
-use Bio::EnsEMBL::Variation::Utils::VEP qw(
-    parse_line
-    vf_to_consequences
-    validate_vf
-    load_dumped_adaptor_cache
-    dump_adaptor_cache
-    get_all_consequences
-    get_slice
-    build_full_cache
-    read_cache_info
-    get_time
-    debug
-    @OUTPUT_COLS
-    @REG_FEAT_TYPES
-);
-
-# global vars
-my $VERSION = '2.2';
-
-# set output autoflush for progress bars
-$| = 1;
-
-# configure from command line opts
-my $config = &configure(scalar @ARGV);
-
-# run the main sub routine
-&main($config);
-
-# this is the main sub-routine - it needs the configured $config hash
-sub main {
-    my $config = shift;
-
-    debug("Starting...") unless defined $config->{quiet};
-
-    my $tr_cache = {};
-    my $rf_cache = {};
-
-    # create a hash to hold slices so we don't get the same one twice
-    my %slice_cache = ();
-
-    my @vfs;
-    my ($vf_count, $total_vf_count);
-    my $in_file_handle = $config->{in_file_handle};
-
-    # initialize line number in config
-    $config->{line_number} = 0;
-
-    # read the file
-    while(<$in_file_handle>) {
-        chomp;
-
-        $config->{line_number}++;
-
-        # header line?
-        next if /^\#/;
-
-        # some lines (pileup) may actually parse out into more than one variant
-        foreach my $vf(@{&parse_line($config, $_)}) {
-
-            # validate the VF
-            next unless validate_vf($config, $vf);
-
-            # now get the slice
-            if(!defined($vf->{slice})) {
-                my $slice;
-
-                # don't get slices if we're using cache
-                # we can steal them from transcript objects later
-                if((!defined($config->{cache}) && !defined($config->{whole_genome})) || defined($config->{check_ref}) || defined($config->{convert})) {
-
-                    # check if we have fetched this slice already
-                    if(defined $slice_cache{$vf->{chr}}) {
-                        $slice = $slice_cache{$vf->{chr}};
-                    }
-
-                    # if not create a new one
-                    else {
-
-                        $slice = &get_slice($config, $vf->{chr});
-
-                        # if failed, warn and skip this line
-                        if(!defined($slice)) {
-                            warn("WARNING: Could not fetch slice named ".$vf->{chr}." on line ".$config->{line_number}."\n") unless defined $config->{quiet};
-                            next;
-                        }
-
-                        # store the hash
-                        $slice_cache{$vf->{chr}} = $slice;
-                    }
-                }
-
-                $vf->{slice} = $slice;
-            }
-
-            # make a name if one doesn't exist
-            $vf->{variation_name} ||= $vf->{chr}.'_'.$vf->{start}.'_'.$vf->{allele_string};
-
-            # jump out to convert here
-            if(defined($config->{convert})) {
-                &convert_vf($config, $vf);
-                next;
-            }
-
-            if(defined $config->{whole_genome}) {
-                push @vfs, $vf;
-                $vf_count++;
-                $total_vf_count++;
-
-                if($vf_count == $config->{buffer_size}) {
-                    debug("Read $vf_count variants into buffer") unless defined($config->{quiet});
-
-                    print_line($config, $_) foreach @{get_all_consequences($config, \@vfs, $tr_cache, $rf_cache)};
-
-                    debug("Processed $total_vf_count total variants") unless defined($config->{quiet});
-
-                    @vfs = ();
-                    $vf_count = 0;
-                }
-            }
-            else {
-                print_line($config, $_) foreach @{vf_to_consequences($config, $vf)};
-                $vf_count++;
-                $total_vf_count++;
-                debug("Processed $vf_count variants") if $vf_count =~ /0$/ && defined($config->{verbose});
-            }
-        }
-    }
-
-    # if in whole-genome mode, finish off the rest of the buffer
-    if(defined $config->{whole_genome} && scalar @vfs) {
-        debug("Read $vf_count variants into buffer") unless defined($config->{quiet});
-
-        print_line($config, $_) foreach @{get_all_consequences($config, \@vfs, $tr_cache, $rf_cache)};
-
-        debug("Processed $total_vf_count total variants") unless defined($config->{quiet});
-    }
-
-    debug("Executed ", defined($Bio::EnsEMBL::DBSQL::StatementHandle::count_queries) ? $Bio::EnsEMBL::DBSQL::StatementHandle::count_queries : 'unknown number of', " SQL statements") if defined($config->{count_queries}) && !defined($config->{quiet});
-
-    debug("Finished!") unless defined $config->{quiet};
-}
-
-# sets up configuration hash that is used throughout the script
-sub configure {
-    my $args = shift;
-
-    my $config = {};
-
-    GetOptions(
-        $config,
-        'help',                    # displays help message
-
-        # input options,
-        'config=s',                # config file name
-        'input_file=s',            # input file name
-        'format=s',                # input file format
-
-        # DB options
-        'species=s',               # species e.g. human, homo_sapiens
-        'registry=s',              # registry file
-        'host=s',                  # database host
-        'port=s',                  # database port
-        'user=s',                  # database user name
-        'password=s',              # database password
-        'db_version=i',            # Ensembl database version to use e.g. 62
-        'genomes',                 # automatically sets DB params for e!Genomes
-        'refseq',                  # use otherfeatures RefSeq DB instead of Ensembl
-        #'no_disconnect',           # disables disconnect_when_inactive
-
-        # runtime options
-        'most_severe',             # only return most severe consequence
-        'summary',                 # only return one line per variation with all consquence types
-        'per_gene',                # only return most severe per gene
-        'buffer_size=i',           # number of variations to read in before analysis
-        'chunk_size=s',            # size in bases of "chunks" used in internal hash structure
-        'failed=i',                # include failed variations when finding existing
-        'no_whole_genome',         # disables now default whole-genome mode
-        'whole_genome',            # proxy for whole genome mode - now just warns user
-        'gp',                      # read coords from GP part of INFO column in VCF (probably only relevant to 1KG)
-        'chr=s',                   # analyse only these chromosomes, e.g. 1-5,10,MT
-        'check_ref',               # check supplied reference allele against DB
-        'check_existing',          # find existing co-located variations
-        'check_alleles',           # only attribute co-located if alleles are the same
-        'check_frequency',         # enable frequency checking
-        'freq_filter=s',           # exclude or include
-        'freq_freq=f',             # frequency to filter on
-        'freq_gt_lt=s',            # gt or lt (greater than or less than)
-        'freq_pop=s',              # population to filter on
-
-        # verbosity options
-        'verbose',                 # print out a bit more info while running
-        'quiet',                   # print nothing to STDOUT (unless using -o stdout)
-        'no_progress',             # don't display progress bars
-
-        # output options
-        'output_file=s',           # output file name
-        'force_overwrite',         # force overwrite of output file if already exists
-        'terms=s',                 # consequence terms to use e.g. NCBI, SO
-        'coding_only',             # only return results for consequences in coding regions
-        'canonical',               # indicates if transcript is canonical
-        'protein',                 # add e! protein ID to extra column
-        'hgnc',                    # add HGNC gene ID to extra column
-        'hgvs',                    # add HGVS names to extra column
-        'sift=s',                  # SIFT predictions
-        'polyphen=s',              # PolyPhen predictions
-        'condel=s',                # Condel predictions
-        'gene',                    # force gene column to be populated (disabled by default, enabled when using cache)
-        'regulatory',              # enable regulatory stuff
-        'convert=s',               # convert input to another format (doesn't run VEP)
-        'no_intergenic',           # don't print out INTERGENIC consequences
-        'gvf',                     # produce gvf output
-
-        # cache stuff
-        'cache',                   # use cache
-        'write_cache',             # enables writing to the cache
-        'build=s',                 # builds cache from DB from scratch; arg is either all (all top-level seqs) or a list of chrs
-        'prefetch',                # prefetch exons, translation, introns, codon table etc for each transcript
-        'strip',                   # strips adaptors etc from objects before caching them
-        'rebuild=s',               # rebuilds cache by reading in existing then redumping - probably don't need to use this any more
-        'dir=s',                   # dir where cache is found (defaults to $HOME/.vep/)
-        'cache_region_size=i',     # size of region in bases for each cache file
-        'no_slice_cache',          # tell API not to cache features on slice
-        'standalone',              # standalone mode uses minimal set of modules installed in same dir, no DB connection
-        'skip_db_check',           # don't compare DB parameters with cached
-        'compress=s',              # by default we use zcat to decompress; user may want to specify gzcat or "gzip -dc"
-
-        # debug
-        'cluck',                   # these two need some mods to Bio::EnsEMBL::DBSQL::StatementHandle to work. Clucks callback trace and SQL
-        'count_queries',           # counts SQL queries executed
-        'admin',                   # allows me to build off public hosts
-        'debug',                   # print out debug info
-    );
-
-    # print usage message if requested or no args supplied
-    if(defined($config->{help}) || !$args) {
-        &usage;
-        exit(0);
-    }
-
-    # config file?
-    if(defined $config->{config}) {
-
-        open CONFIG, $config->{config} or die "ERROR: Could not open config file \"".$config->{config}."\"\n";
-
-        while(<CONFIG>) {
-            next if /^\#/;
-            my ($key, $value) = split /\s+|\=/;
-            $key =~ s/^\-//g;
-            $config->{$key} = $value unless defined $config->{$key};
-        }
-
-        close CONFIG;
-    }
-
-    # can't be both quiet and verbose
-    die "ERROR: Can't be both quiet and verbose!" if defined($config->{quiet}) && defined($config->{verbose});
-
-    # check file format
-    if(defined $config->{format}) {
-        die "ERROR: Unrecognised input format specified \"".$config->{format}."\"\n" unless $config->{format} =~ /pileup|vcf|guess|hgvs|ensembl|id/i;
-    }
-
-    # check convert format
-    if(defined $config->{convert}) {
-        die "ERROR: Unrecognised output format for conversion specified \"".$config->{convert}."\"\n" unless $config->{convert} =~ /vcf|ensembl|pileup/i;
-    }
-
-    # connection settings for Ensembl Genomes
-    if($config->{genomes}) {
-        $config->{host} ||= 'mysql.ebi.ac.uk';
-        $config->{port} ||= 4157;
-    }
-
-    # connection settings for main Ensembl
-    else {
-        $config->{species} ||= "homo_sapiens";
-        $config->{host}    ||= 'ensembldb.ensembl.org';
-        $config->{port}    ||= 5306;
-    }
-
-    # refseq or core?
-    if(defined($config->{refseq})) {
-        die "ERROR: SIFT, PolyPhen and Condel predictions not available fore RefSeq transcripts" if defined $config->{sift} || defined $config->{polyphen} || defined $config->{condel};
-
-        $config->{core_type} = 'otherfeatures';
-    }
-    else {
-        $config->{core_type} = 'core';
-    }
-
-    # output term
-    if(defined $config->{terms}) {
-        die "ERROR: Unrecognised consequence term type specified \"".$config->{terms}."\" - must be one of ensembl, so, ncbi\n" unless $config->{terms} =~ /ensembl|display|so|ncbi/i;
-        if($config->{terms} =~ /ensembl|display/i) {
-            $config->{terms} = 'display';
-        }
-        else {
-            $config->{terms} = uc($config->{terms});
-        }
-    }
-
-    # check nsSNP tools
-    foreach my $tool(grep {defined $config->{lc($_)}} qw(SIFT PolyPhen Condel)) {
-        die "ERROR: Unrecognised option for $tool \"", $config->{lc($tool)}, "\" - must be one of p (prediction), s (score) or b (both)\n" unless $config->{lc($tool)} =~ /^(s|p|b)/;
-
-        die "ERROR: $tool not available for this species\n" unless $config->{species} =~ /human|homo/i;
-
-        die "ERROR: $tool not available in standalone mode\n" if defined($config->{standalone});
-
-        # use V2 of the Condel algorithm, possibly gives fewer false positives
-        if($tool eq 'Condel' && $config->{lc($tool)} =~ /1$/) {
-            $Bio::EnsEMBL::Variation::Utils::Condel::USE_V2 = 0;
-        }
-    }
-
-    # force quiet if outputting to STDOUT
-    if(defined($config->{output_file}) && $config->{output_file} =~ /stdout/i) {
-        delete $config->{verbose} if defined($config->{verbose});
-        $config->{quiet} = 1;
-    }
-
-    # summarise options if verbose
-    if(defined $config->{verbose}) {
-        my $header =<<INTRO;
-#----------------------------------#
-# ENSEMBL VARIANT EFFECT PREDICTOR #
-#----------------------------------#
-
-version $VERSION
-
-By Will McLaren (wm2\@ebi.ac.uk)
-
-Configuration options:
-
-INTRO
-        print $header;
-
-        my $max_length = (sort {$a <=> $b} map {length($_)} keys %$config)[-1];
-
-        foreach my $key(sort keys %$config) {
-            print $key.(' ' x (($max_length - length($key)) + 4)).$config->{$key}."\n";
-        }
-
-        print "\n".("-" x 20)."\n\n";
-    }
-
-    # set defaults
-    $config->{user}              ||= 'anonymous';
-    $config->{buffer_size}       ||= 5000;
-    $config->{chunk_size}        ||= '50kb';
-    $config->{output_file}       ||= "variant_effect_output.txt";
-    $config->{tmpdir}            ||= '/tmp';
-    $config->{format}            ||= 'guess';
-    $config->{terms}             ||= 'display';
-    $config->{gene}              ||= 1 unless defined($config->{whole_genome});
-    $config->{cache_region_size} ||= 1000000;
-    $config->{dir}               ||= join '/', ($ENV{'HOME'}, '.vep');
-    $config->{compress}          ||= 'zcat';
-
-    # frequency filtering
-    if(defined($config->{check_frequency})) {
-        foreach my $flag(qw(freq_freq freq_filter freq_pop freq_gt_lt)) {
-            die "ERROR: To use --check_frequency you must also specify flag --$flag" unless defined $config->{$flag};
-        }
-
-        # need to set check_existing
-        $config->{check_existing} = 1;
-    }
-
-    $config->{check_existing} = 1 if defined $config->{check_alleles};
-
-    # warn users still using whole_genome flag
-    if(defined($config->{whole_genome})) {
-        debug("INFO: Whole-genome mode is now the default run-mode for the script. To disable it, use --no_whole_genome") unless defined($config->{quiet});
-    }
-
-    $config->{whole_genome}      = 1 unless defined $config->{no_whole_genome};
-    $config->{include_failed}    = 1 unless defined $config->{include_failed};
-    $config->{chunk_size}        =~ s/mb?/000000/i;
-    $config->{chunk_size}        =~ s/kb?/000/i;
-    $config->{cache_region_size} =~ s/mb?/000000/i;
-    $config->{cache_region_size} =~ s/kb?/000/i;
-
-    # cluck and display executed SQL?
-    $Bio::EnsEMBL::DBSQL::StatementHandle::cluck = 1 if defined($config->{cluck});
-
-    # standalone needs cache, can't use HGVS
-    if(defined($config->{standalone})) {
-        $config->{cache} = 1;
-
-        die("ERROR: Cannot generate HGVS coordinates in standalone mode") if defined($config->{hgvs});
-        die("ERROR: Cannot use HGVS as input in standalone mode") if $config->{format} eq 'hgvs';
-        die("ERROR: Cannot use variant identifiers as input in standalone mode") if $config->{format} eq 'id';
-        die("ERROR: Cannot do frequency filtering in standalone mode") if defined($config->{check_frequency});
-    }
-
-    # write_cache needs cache
-    $config->{cache} = 1 if defined $config->{write_cache};
-
-    # no_slice_cache, prefetch and whole_genome have to be on to use cache
-    if(defined($config->{cache})) {
-        $config->{prefetch} = 1;
-        $config->{no_slice_cache} = 1;
-        $config->{whole_genome} = 1;
-        $config->{strip} = 1;
-    }
-
-    $config->{build} = $config->{rebuild} if defined($config->{rebuild});
-
-    # force options for full build
-    if(defined($config->{build})) {
-        $config->{prefetch} = 1;
-        $config->{gene} = 1;
-        $config->{hgnc} = 1;
-        $config->{no_slice_cache} = 1;
-        $config->{cache} = 1;
-        $config->{strip} = 1;
-        $config->{write_cache} = 1;
-    }
-
-    # connect to databases
-    $config->{reg} = &connect_to_dbs($config);
-
-    # complete dir with species name and db_version
-    $config->{dir} .= '/'.(
-        join '/', (
-            defined($config->{standalone}) ? $config->{species} : ($config->{reg}->get_alias($config->{species}) || $config->{species}),
-            $config->{db_version} || $config->{reg}->software_version
-        )
-    );
-
-    if(defined($config->{cache})) {
-        # read cache info
-        if(read_cache_info($config)) {
-            debug("Read existing cache info") unless defined $config->{quiet};
-        }
-    }
-
-    # include regulatory modules if requested
-    if(defined($config->{regulatory})) {
-        # do the use statements here so that users don't have to have the
-        # funcgen API install to use the rest of the script
-        eval q{
-            use Bio::EnsEMBL::Funcgen::DBSQL::RegulatoryFeatureAdaptor;
-            use Bio::EnsEMBL::Funcgen::DBSQL::MotifFeatureAdaptor;
-            use Bio::EnsEMBL::Funcgen::MotifFeature;
-            use Bio::EnsEMBL::Funcgen::RegulatoryFeature;
-            use Bio::EnsEMBL::Funcgen::BindingMatrix;
-        };
-
-        if($@) {
-            die("ERROR: Ensembl Funcgen API must be installed to use --regulatory\n");
-        }
-    }
-
-    # warn user cache directory doesn't exist
-    if(!-e $config->{dir}) {
-
-        # if using write_cache
-        if(defined($config->{write_cache})) {
-            debug("INFO: Cache directory ", $config->{dir}, " not found - it will be created") unless defined($config->{quiet});
-        }
-
-        # want to read cache, not found
-        elsif(defined($config->{cache})) {
-            die("ERROR: Cache directory ", $config->{dir}, " not found");
-        }
-    }
-
-    # suppress warnings that the FeatureAdpators spit if using no_slice_cache
-    Bio::EnsEMBL::Utils::Exception::verbose(1999) if defined($config->{no_slice_cache});
-
-    # get adaptors
-    if(defined($config->{cache}) && !defined($config->{write_cache})) {
-
-        # try and load adaptors from cache
-        if(!&load_dumped_adaptor_cache($config)) {
-            &get_adaptors($config);
-            &dump_adaptor_cache($config) if defined($config->{write_cache});
-        }
-
-        # check cached adaptors match DB params
-        else {
-            my $dbc = $config->{sa}->{dbc};
-
-            my $ok = 1;
-
-            if($dbc->{_host} ne $config->{host}) {
-
-                # ens-livemirror, useastdb and ensembldb should all have identical DBs
-                unless(
-                    (
-                        $dbc->{_host} eq 'ens-livemirror'
-                        || $dbc->{_host} eq 'ensembldb.ensembl.org'
-                        || $dbc->{_host} eq 'useastdb.ensembl.org'
-                    ) && (
-                        $config->{host} eq 'ens-livemirror'
-                        || $config->{host} eq 'ensembldb.ensembl.org'
-                        || $config->{host} eq 'useastdb.ensembl.org'
-                    )
-                ) {
-                    $ok = 0;
-                }
-
-                # but we still need to reconnect
-                debug("INFO: Defined host ", $config->{host}, " is different from cached ", $dbc->{_host}, " - reconnecting to host") unless defined($config->{quiet});
-
-                &get_adaptors($config);
-            }
-
-            if(!$ok) {
-                if(defined($config->{skip_db_check})) {
-                    debug("INFO: Defined host ", $config->{host}, " is different from cached ", $dbc->{_host}) unless defined($config->{quiet});
-                }
-                else {
-                    die "ERROR: Defined host ", $config->{host}, " is different from cached ", $dbc->{_host}, ". If you are sure this is OK, rerun with -skip_db_check flag set";
-                }
-            }
-        }
-    }
-    else {
-        &get_adaptors($config);
-        &dump_adaptor_cache($config) if defined($config->{write_cache})
-    }
-
-    # reg adaptors (only fetches if not retrieved from cache already)
-    &get_reg_adaptors($config) if defined($config->{regulatory});
-
-    # get terminal width for progress bars
-    unless(defined($config->{quiet})) {
-        my $width;
-
-        # module may not be installed
-        eval q{
-            use Term::ReadKey;
-        };
-
-        if(!$@) {
-            my ($w, $h);
-
-            # module may be installed, but e.g.
-            eval {
-                ($w, $h) = GetTerminalSize();
-            };
-
-            $width = $w if defined $w;
-        }
-
-        $width ||= 60;
-        $width -= 12;
-        $config->{terminal_width} = $width;
-    }
-
-    # jump out to build cache if requested
-    if(defined($config->{build})) {
-
-        if($config->{host} =~ /^(ensembl|useast)db\.ensembl\.org$/ && !defined($config->{admin})) {
-            die("ERROR: Cannot build cache using public database server ", $config->{host}, "\n");
-        }
-
-        # build the cache
-        debug("Building cache for ".$config->{species}) unless defined($config->{quiet});
-        build_full_cache($config);
-
-        # exit script
-        debug("Finished building cache") unless defined($config->{quiet});
-        exit(0);
-    }
-
-    # warn user DB will be used for SIFT/PolyPhen/Condel/HGVS/frequency
-    if(defined($config->{cache})) {
-
-        # these two def depend on DB
-        foreach my $param(grep {defined $config->{$_}} qw(hgvs check_frequency)) {
-            debug("INFO: Database will be accessed when using --$param") unless defined($config->{quiet});
-        }
-
-        # as does using HGVS or IDs as input
-        debug("INFO: Database will be accessed when using --format ", $config->{format}) if ($config->{format} eq 'id' || $config->{format} eq 'hgvs') && !defined($config->{quiet});
-
-        # the rest may be in the cache
-        foreach my $param(grep {defined $config->{$_}} qw(sift polyphen condel regulatory)) {
-            next if defined($config->{'cache_'.$param});
-            debug("INFO: Database will be accessed when using --$param; consider using the complete cache containing $param data (see documentation for details)") unless defined($config->{quiet});
-        }
-    }
-
-    # get list of chrs if supplied
-    if(defined($config->{chr})) {
-        my %chrs;
-
-        foreach my $val(split /\,/, $config->{chr}) {
-            my @nnn = split /\-/, $val;
-
-            foreach my $chr($nnn[0]..$nnn[-1]) {
-                $chrs{$chr} = 1;
-            }
-        }
-
-        $config->{chr} = \%chrs;
-    }
-
-    # get input file handle
-    $config->{in_file_handle} = &get_in_file_handle($config);
-
-    # configure output file
-    $config->{out_file_handle} = &get_out_file_handle($config);
-
-    return $config;
-}
-
-# connects to DBs; in standalone mode this just loads registry module
-sub connect_to_dbs {
-    my $config = shift;
-
-    # get registry
-    my $reg = 'Bio::EnsEMBL::Registry';
-
-    unless(defined($config->{standalone})) {
-        # load DB options from registry file if given
-        if(defined($config->{registry})) {
-            debug("Loading DB config from registry file ", $config->{registry}) unless defined($config->{quiet});
-            $reg->load_all(
-                $config->{registry},
-                $config->{verbose},
-                undef,
-                $config->{no_slice_cache}
-            );
-        }
-
-        # otherwise manually connect to DB server
-        else {
-            $reg->load_registry_from_db(
-                -host       => $config->{host},
-                -user       => $config->{user},
-                -pass       => $config->{password},
-                -port       => $config->{port},
-                -db_version => $config->{db_version},
-                -species    => $config->{species} =~ /^[a-z]+\_[a-z]+/i ? $config->{species} : undef,
-                -verbose    => $config->{verbose},
-                -no_cache   => $config->{no_slice_cache},
-            );
-        }
-
-        eval { $reg->set_reconnect_when_lost() };
-
-        if(defined($config->{verbose})) {
-            # get a meta container adaptors to check version
-            my $core_mca = $reg->get_adaptor($config->{species}, 'core', 'metacontainer');
-            my $var_mca = $reg->get_adaptor($config->{species}, 'variation', 'metacontainer');
-
-            if($core_mca && $var_mca) {
-                debug(
-                    "Connected to core version ", $core_mca->get_schema_version, " database ",
-                    "and variation version ", $var_mca->get_schema_version, " database"
-                );
-            }
-        }
-    }
-
-    return $reg;
-}
-
-# get adaptors from DB
-sub get_adaptors {
-    my $config = shift;
-
-    die "ERROR: No registry" unless defined $config->{reg};
-
-    $config->{vfa}   = $config->{reg}->get_adaptor($config->{species}, 'variation', 'variationfeature');
-    $config->{tva}   = $config->{reg}->get_adaptor($config->{species}, 'variation', 'transcriptvariation');
-    $config->{pfpma} = $config->{reg}->get_adaptor($config->{species}, 'variation', 'proteinfunctionpredictionmatrix');
-    $config->{va}    = $config->{reg}->get_adaptor($config->{species}, 'variation', 'variation');
-
-    # get fake ones for species with no var DB
-    if(!defined($config->{vfa})) {
-        $config->{vfa} = Bio::EnsEMBL::Variation::DBSQL::VariationFeatureAdaptor->new_fake($config->{species});
-        $config->{tva} = Bio::EnsEMBL::Variation::DBSQL::TranscriptVariationAdaptor->new_fake($config->{species});
-    }
-    else {
-        $config->{vfa}->db->include_failed_variations($config->{include_failed}) if defined($config->{vfa}->db) && $config->{vfa}->db->can('include_failed_variations');
-    }
-
-    $config->{sa}  = $config->{reg}->get_adaptor($config->{species}, $config->{core_type}, 'slice');
-    $config->{ga}  = $config->{reg}->get_adaptor($config->{species}, $config->{core_type}, 'gene');
-    $config->{ta}  = $config->{reg}->get_adaptor($config->{species}, $config->{core_type}, 'transcript');
-    $config->{mca} = $config->{reg}->get_adaptor($config->{species}, $config->{core_type}, 'metacontainer');
-    $config->{csa} = $config->{reg}->get_adaptor($config->{species}, $config->{core_type}, 'coordsystem');
-
-    # cache schema version
-    $config->{mca}->get_schema_version if defined $config->{mca};
-
-    # check we got slice adaptor - can't continue without a core DB
-    die("ERROR: Could not connect to core database\n") unless defined $config->{sa};
-}
-
-# gets regulatory adaptors
-sub get_reg_adaptors {
-    my $config = shift;
-
-    foreach my $type(@REG_FEAT_TYPES) {
-        next if defined($config->{$type.'_adaptor'});
-
-        my $adaptor = $config->{reg}->get_adaptor($config->{species}, 'funcgen', $type);
-        if(defined($adaptor)) {
-            $config->{$type.'_adaptor'} = $adaptor;
-        }
-        else {
-            delete $config->{regulatory};
-            last;
-        }
-    }
-}
-
-# gets file handle for input
-sub get_in_file_handle {
-    my $config = shift;
-
-    # define the filehandle to read input from
-    my $in_file_handle = new FileHandle;
-
-    if(defined($config->{input_file})) {
-
-        # check defined input file exists
-        die("ERROR: Could not find input file ", $config->{input_file}, "\n") unless -e $config->{input_file};
-
-        if($config->{input_file} =~ /\.gz$/){
-            $in_file_handle->open($config->{compress}." ". $config->{input_file} . " | " ) or die("ERROR: Could not read from input file ", $config->{input_file}, "\n");
-        }
-        else {
-            $in_file_handle->open( $config->{input_file} ) or die("ERROR: Could not read from input file ", $config->{input_file}, "\n");
-        }
-    }
-
-    # no file specified - try to read data off command line
-    else {
-        $in_file_handle = 'STDIN';
-        debug("Reading input from STDIN (or maybe you forgot to specify an input file?)...") unless defined $config->{quiet};
-    }
-
-    return $in_file_handle;
-}
-
-# gets file handle for output and adds header
-sub get_out_file_handle {
-    my $config = shift;
-
-    # define filehandle to write to
-    my $out_file_handle = new FileHandle;
-
-    # check if file exists
-    if(-e $config->{output_file} && !defined($config->{force_overwrite})) {
-        die("ERROR: Output file ", $config->{output_file}, " already exists. Specify a different output file with --output_file or overwrite existing file with --force_overwrite\n");
-    }
-
-    if($config->{output_file} =~ /stdout/i) {
-        $out_file_handle = *STDOUT;
-    }
-    else {
-        $out_file_handle->open(">".$config->{output_file}) or die("ERROR: Could not write to output file ", $config->{output_file}, "\n");
-    }
-
-    # file conversion, don't want to add normal headers
-    if(defined($config->{convert})) {
-        # header for VCF
-        if($config->{convert} =~ /vcf/i) {
-            print $out_file_handle join "\t", (
-                '#CHROM',
-                'POS',
-                'ID',
-                'REF',
-                'ALT',
-                'QUAL',
-                'FILTER',
-                'INFO'
-            );
-            print $out_file_handle "\n";
-        }
-
-        return $out_file_handle;
-    }
-
-    # GVF output, no header
-    elsif(defined($config->{gvf})) {
-        return $out_file_handle;
-    }
-
-    # make header
-    my $time = &get_time;
-    my $db_string = $config->{mca}->dbc->dbname." on ".$config->{mca}->dbc->host if defined $config->{mca};
-    $db_string .= "\n## Using cache in ".$config->{dir} if defined($config->{cache});
-    my $version_string =
-        "Using API version ".$config->{reg}->software_version.
-        ", DB version ".(defined $config->{mca} && $config->{mca}->get_schema_version ? $config->{mca}->get_schema_version : '?');
-
-    my $header =<<HEAD;
-## ENSEMBL VARIANT EFFECT PREDICTOR v$VERSION
-## Output produced at $time
-## Connected to $db_string
-## $version_string
-## Extra column keys:
-## CANONICAL    : Indicates if transcript is canonical for this gene
-## HGNC         : HGNC gene identifier
-## ENSP         : Ensembl protein identifer
-## HGVSc        : HGVS coding sequence name
-## HGVSp        : HGVS protein sequence name
-## SIFT         : SIFT prediction
-## PolyPhen     : PolyPhen prediction
-## Condel       : Condel SIFT/PolyPhen consensus prediction
-## MATRIX       : The source and identifier of a transcription factor binding profile aligned at this position
-## HIGH_INF_POS : A flag indicating if the variant falls in a high information position of a transcription factor binding profile
-HEAD
-
-    # add headers
-    print $out_file_handle $header;
-
-    # add column headers
-    print $out_file_handle '#', (join "\t", @OUTPUT_COLS);
-    print $out_file_handle "\n";
-
-    return $out_file_handle;
-}
-
-# convert a variation feature to a line of output
-sub convert_vf {
-    my $config = shift;
-    my $vf = shift;
-
-    my $convert_method = 'convert_to_'.lc($config->{convert});
-    my $method_ref   = \&$convert_method;
-
-    my $line = &$method_ref($config, $vf);
-    my $handle = $config->{out_file_handle};
-
-    if(scalar @$line) {
-        print $handle join "\t", @$line;
-        print $handle "\n";
-    }
-}
-
-# converts to Ensembl format
-sub convert_to_ensembl {
-    my $config = shift;
-    my $vf = shift;
-
-    return [
-        $vf->{chr} || $vf->seq_region_name,
-        $vf->start,
-        $vf->end,
-        $vf->allele_string,
-        $vf->strand,
-        $vf->variation_name
-    ];
-}
-
-# converts to VCF format
-sub convert_to_vcf {
-    my $config = shift;
-    my $vf = shift;
-
-    # look for imbalance in the allele string
-    my %allele_lengths;
-    my @alleles = split /\//, $vf->allele_string;
-
-    foreach my $allele(@alleles) {
-        $allele =~ s/\-//g;
-        $allele_lengths{length($allele)} = 1;
-    }
-
-    # in/del/unbalanced
-    if(scalar keys %allele_lengths > 1) {
-
-        # we need the ref base before the variation
-        # default to N in case we can't get it
-        my $prev_base = 'N';
-
-        unless(defined($config->{cache})) {
-            my $slice = $vf->slice->sub_Slice($vf->start - 1, $vf->start - 1);
-            $prev_base = $slice->seq if defined($slice);
-        }
-
-        for my $i(0..$#alleles) {
-            $alleles[$i] =~ s/\-//g;
-            $alleles[$i] = $prev_base.$alleles[$i];
-        }
-
-        return [
-            $vf->{chr} || $vf->seq_region_name,
-            $vf->start - 1,
-            $vf->variation_name,
-            shift @alleles,
-            (join ",", @alleles),
-            '.', '.', '.'
-        ];
-
-    }
-
-    # balanced sub
-    else {
-        return [
-            $vf->{chr} || $vf->seq_region_name,
-            $vf->start,
-            $vf->variation_name,
-            shift @alleles,
-            (join ",", @alleles),
-            '.', '.', '.'
-        ];
-    }
-}
-
-
-# converts to pileup format
-sub convert_to_pileup {
-    my $config = shift;
-    my $vf = shift;
-
-    # look for imbalance in the allele string
-    my %allele_lengths;
-    my @alleles = split /\//, $vf->allele_string;
-
-    foreach my $allele(@alleles) {
-        $allele =~ s/\-//g;
-        $allele_lengths{length($allele)} = 1;
-    }
-
-    # in/del
-    if(scalar keys %allele_lengths > 1) {
-
-        if($vf->allele_string =~ /\-/) {
-
-            # insertion?
-            if($alleles[0] eq '-') {
-                shift @alleles;
-
-                for my $i(0..$#alleles) {
-                    $alleles[$i] =~ s/\-//g;
-                    $alleles[$i] = '+'.$alleles[$i];
-                }
-            }
-
-            else {
-                @alleles = grep {$_ ne '-'} @alleles;
-
-                for my $i(0..$#alleles) {
-                    $alleles[$i] =~ s/\-//g;
-                    $alleles[$i] = '-'.$alleles[$i];
-                }
-            }
-
-            @alleles = grep {$_ ne '-' && $_ ne '+'} @alleles;
-
-            return [
-                $vf->{chr} || $vf->seq_region_name,
-                $vf->start - 1,
-                '*',
-                (join "/", @alleles),
-            ];
-        }
-
-        else {
-            warn "WARNING: Unable to convert variant to pileup format on line number ", $config->{line_number} unless defined($config->{quiet});
-            return [];
-        }
-
-    }
-
-    # balanced sub
-    else {
-        return [
-            $vf->{chr} || $vf->seq_region_name,
-            $vf->start,
-            shift @alleles,
-            (join "/", @alleles),
-        ];
-    }
-}
-
-# prints a line of output from the hash
-sub print_line {
-    my $config = shift;
-    my $line = shift;
-    return unless defined($line);
-
-    my $output;
-
-    # normal
-    if(ref($line) eq 'HASH') {
-        $line->{Extra} = join ';', map { $_.'='.$line->{Extra}->{$_} } keys %{ $line->{Extra} || {} };
-        $output = join "\t", map { $line->{$_} || '-' } @OUTPUT_COLS;
-    }
-
-    # gvf
-    else {
-        $output = $line;
-    }
-
-    my $fh = $config->{out_file_handle};
-    print $fh "$output\n";
-}
-
-# outputs usage message
-sub usage {
-    my $usage =<<END;
-#----------------------------------#
-# ENSEMBL VARIANT EFFECT PREDICTOR #
-#----------------------------------#
-
-version $VERSION
-
-By Will McLaren (wm2\@ebi.ac.uk)
-
-http://www.ensembl.org/info/docs/variation/vep/vep_script.html
-
-Usage:
-perl variant_effect_predictor.pl [arguments]
-
-Options
-=======
-
---help                 Display this message and quit
---verbose              Display verbose output as the script runs [default: off]
---quiet                Suppress status and warning messages [default: off]
---no_progress          Suppress progress bars [default: off]
-
---config               Load configuration from file. Any command line options
-                       specified overwrite those in the file [default: off]
-
--i | --input_file      Input file - if not specified, reads from STDIN. Files
-                       may be gzip compressed.
---format               Specify input file format - one of "ensembl", "pileup",
-                       "vcf", "hgvs", "id" or "guess" to try and work out format.
--o | --output_file     Output file. Write to STDOUT by specifying -o STDOUT - this
-                       will force --quiet [default: "variant_effect_output.txt"]
---force_overwrite      Force overwriting of output file [default: quit if file
-                       exists]
-
---species [species]    Species to use [default: "human"]
-
--t | --terms           Type of consequence terms to output - one of "ensembl", "SO",
-                       "NCBI" [default: ensembl]
-
---sift=[p|s|b]         Add SIFT [p]rediction, [s]core or [b]oth [default: off]
---polyphen=[p|s|b]     Add PolyPhen [p]rediction, [s]core or [b]oth [default: off]
---condel=[p|s|b]       Add Condel SIFT/PolyPhen consensus [p]rediction, [s]core or
-                       [b]oth. Add 1 (e.g. b1) to option to use old Condel algorithm
-                       [default: off]
-
-NB: SIFT, PolyPhen and Condel predictions are currently available for human only
-
---regulatory           Look for overlaps with regulatory regions. The script can
-                       also call if a variant falls in a high information position
-                       within a transcription factor binding site. Output lines have
-                       a Feature type of RegulatoryFeature or MotifFeature
-                       [default: off]
-
-NB: Regulatory consequences are currently available for human and mouse only
-
---hgnc                 If specified, HGNC gene identifiers are output alongside the
-                       Ensembl Gene identifier [default: off]
---hgvs                 Output HGVS identifiers (coding and protein). Requires database
-                       connection [default: off]
---protein              Output Ensembl protein identifer [default: off]
---gene                 Force output of Ensembl gene identifer - disabled by default
-                       unless using --cache or --no_whole_genome [default: off]
---canonical            Indicate if the transcript for this consequence is the canonical
-                       transcript for this gene [default: off]
-
---coding_only          Only return consequences that fall in the coding region of
-                       transcripts [default: off]
---most_severe          Ouptut only the most severe consequence per variation.
-                       Transcript-specific columns will be left blank. [default: off]
---summary              Output only a comma-separated list of all consequences per
-                       variation. Transcript-specific columns will be left blank.
-                       [default: off]
---per_gene             Output only the most severe consequence per gene. Where more
-                       than one transcript has the same consequence, the transcript
-                       chosen is arbitrary. [default: off]
-
-
---check_ref            If specified, checks supplied reference allele against stored
-                       entry in Ensembl Core database [default: off]
---check_existing       If specified, checks for existing co-located variations in the
-                       Ensembl Variation database [default: off]
---check_alleles        If specified, the alleles of existing co-located variations
-                       are compared to the input; an existing variation will only
-                       be reported if no novel allele is in the input (strand is
-                       accounted for) [default: off]
-
---no_intergenic        Excludes intergenic consequences from the output [default: off]
-
---check_frequency      Turns on frequency filtering. Use this to include or exclude
-                       variants based on the frequency of co-located existing
-                       variants in the Ensembl Variation database. You must also
-                       specify all of the following --freq flags [default: off]
---freq_pop [pop]       Name of the population to use e.g. hapmap_ceu for CEU HapMap,
-                       1kg_yri for YRI 1000 genomes. See documentation for more
-                       details
---freq_freq [freq]     Frequency to use in filter. Must be a number between 0 and 0.5
---freq_gt_lt [gt|lt]   Specify whether the frequency should be greater than (gt) or
-                       less than (lt) --freq_freq
---freq_filter          Specify whether variants that pass the above should be included
-  [exclude|include]    or excluded from analysis
-
---chr [list]           Select a subset of chromosomes to analyse from your file. Any
-                       data not on this chromosome in the input will be skipped. The
-                       list can be comma separated, with "-" characters representing
-                       a range e.g. 1-5,8,15,X [default: off]
---gp                   If specified, tries to read GRCh37 position from GP field in the
-                       INFO column of a VCF file. Only applies when VCF is the input
-                       format and human is the species [default: off]
-
---convert              Convert the input file to the output format specified.
-  [ensembl|vcf|pileup] Converted output is written to the file specified in
-                       --output_file. No consequence calculation is carried out when
-                       doing file conversion. [default: off]
-
---refseq               Use the otherfeatures database to retrieve transcripts - this
-                       database contains RefSeq transcripts (as well as CCDS and
-                       Ensembl EST alignments) [default: off]
---host                 Manually define database host [default: "ensembldb.ensembl.org"]
--u | --user            Database username [default: "anonymous"]
---port                 Database port [default: 5306]
---password             Database password [default: no password]
---genomes              Sets DB connection params for Ensembl Genomes [default: off]
---registry             Registry file to use defines DB connections [default: off]
-                       Defining a registry file overrides above connection settings.
---db_version=[number]  Force script to load DBs from a specific Ensembl version. Not
-                       advised due to likely incompatibilities between API and DB
-
---no_whole_genome      Run in old-style, non-whole genome mode [default: off]
---buffer_size          Sets the number of variants sent in each batch [default: 5000]
-                       Increasing buffer size can retrieve results more quickly
-                       but requires more memory. Only applies to whole genome mode.
-
---cache                Enables read-only use of cache [default: off]
---dir [directory]      Specify the base cache directory to use [default: "\$HOME/.vep/"]
---write_cache          Enable writing to cache [default: off]
---build [all|list]     Build a complete cache for the selected species. Build for all
-                       chromosomes with --build all, or a list of chromosomes (see
-                       --chr). DO NOT USE WHEN CONNECTED TO PUBLIC DB SERVERS AS THIS
-                       VIOLATES OUR FAIR USAGE POLICY [default: off]
-
---compress             Specify utility to decompress cache files - may be "gzcat" or
-                       "gzip -dc" Only use if default does not work [default: zcat]
-
---skip_db_check        ADVANCED! Force the script to use a cache built from a different
-                       database than specified with --host. Only use this if you are
-                       sure the hosts are compatible (e.g. ensembldb.ensembl.org and
-                       useastdb.ensembl.org) [default: off]
---cache_region_size    ADVANCED! The size in base-pairs of the region covered by one
-                       file in the cache. [default: 1MB]
-END
-
-    print $usage;
-}