#!/usr/bin/env perl
use strict;
#use warnings;
use List::Util qw(sum);

die "useage:perl $0 input out tag_out project sample_type pipeline" unless @ARGV == 6;
my ($input, $out, $tag_out, $project, $sample_type, $pipeline) = @ARGV;

# open OUT, ">$**.hg19_multianno_filter.txt";
open OUT, "> $out";
# open OUT1, ">**.hg19_multianno_tag.txt";
open TAG_OUT, ">$tag_out";

if (-z $input) {
    print "文件 $input 为空 \n";
    exit(0); # 正常退出脚本
}

open IN, "$input";
my $head = <IN>;

my @columns = split("\t", $head);
my $new_head = join("\t", @columns[0 .. 6], "Freq", @columns[7 .. 20, 23, 28, 32, 50, 56, 62, 101, 102], "process");

my $head_key;
if ($pipeline eq 'somatic') {
    $head_key = 'Validated';
}
elsif ($pipeline eq 'hotspot') {
    $head_key = 'Validated';
}
elsif ($pipeline eq 'germline') {
    $head_key = 'ClinicalSign';
}
else {
    die "useage: pipeline must be 'somatic' or 'germline' or 'hotspot'";
}

print OUT "$head_key\t$new_head\n";
print TAG_OUT "TAG\t$new_head\n";

my %blacklist = blacklist();
my @mut_gene_list = mut_gene();
my %transcript = transcript();

while (<IN>) {
    chomp;
    my @line = split(/\t/, $_);
    my $freq = ($line[102] =~ /AF=([\d.]+)/) ? $1 : die "AF value not found";
    my $filters = split(";", $line[101]);
    my $gene = (split(";", $line[6]))[0];

    my @reason;
    # 黑名单
    if (exists $blacklist{join("_", @line[0 .. 4])}) {
        push @reason, 'blacklist';
    }

    # 是否检测
    if ((@mut_gene_list) and !(grep {$_ eq $gene} @mut_gene_list)) {
        push @reason, 'notarget_gene';
    }

    # 人群频率
    if (grep {$_ > 0.01} @line[17, 18, 19, 20, 23, 28, 32]) {
        push @reason, 'common_snp';
    }

    # ExonicFunc.refGene 过滤同义突变，未知突变
    if ($line[8] eq "synonymous SNV" or $line[8] eq "unknown") {
        push @reason, 'synonymous';
    }

    # CLNSIG benign
    if ($line[16] =~ /benign/i and $line[16] !~ /pathogenic|Affects|association|Conflicting|sensitivity|drug|other|risk|protective|Uncertain|not_provided|\./i) {
        push @reason, 'benign';
    }

    # 不是pass 低频的； 或者 0.02  < 0.05 之间 个数大于2
    if ($line[101] ne 'PASS' and ($freq < 0.02 or ($freq >= 0.02 and $freq < 0.05 and $filters >= 2))) {
        push @reason, 'byfilter';
    }

    # cfdna 样本
    if ($sample_type eq 'c') {
        # 低频的 cosmic91 无记录的
        if ($freq < 0.01 and $line[11] eq '.') {
            push @reason, 'cfdna_lowfreq_cosmic';
        }

        # 低频的；cosmic91 只有1条以内的
        if ($line[11] =~ /OCCURENCE=(\S+)/) {
            my $cosmic = $1;
            $cosmic =~ s/\(\S+?\)//g;
            my @cosmic = split(",", $cosmic);
            $cosmic = sum @cosmic;
            if ($freq < 0.01 and $cosmic <= 1) {
                push @reason, 'cfdna_lowfreq_cosmic1';
            }
        }
    }

    if ($line[9] eq '.') {
        # splicing 位点 或者 MET的 intron 位点
        if ($line[5] =~ /splicing/ or ($line[5] =~ /intron/ and $gene eq "MET")) {
            my @hgvs = split(/;/, $line[7]);
            my $hgvs = $hgvs[0];
            my $transcript = $transcript{$gene} if (exists $transcript{$gene});
            if (grep {/$transcript/} @hgvs) {
                $hgvs = (grep {/$transcript/} @hgvs)[0];
            }
            $hgvs =~ /(\S+):exon(\d+):c\.(\S+)$/;
            my $spl = $3;
            # splicing 位点 的前后 1-2bp 的 或者 MET的基因
            if ($spl =~ /\d+[\+|\-][1|2]\D+/) {
                $line[9] = join(":", ($gene, $hgvs));
            }
            elsif ($gene eq "MET") {
                $line[9] = join(":", ($gene, "exon14", "c.xxx"));
                $line[8] = 'skipping'
            }
            else {
                push @reason, 'not_need_spl';
            }
        }
        else {
            push @reason, 'not_need';
        }

    }
    else {
        my @hgvs = split(/,/, $line[9]);
        my $hgvs = $hgvs[0];
        my $transcript_gene;
        $transcript_gene = $transcript{$gene} if (exists $transcript{$gene});
        if (grep {/$transcript_gene/} @hgvs) {
            $hgvs = (grep {/$transcript_gene/} @hgvs)[0];
        }
        $line[9] = $hgvs;
    }

    # hotspot 不过滤但是修改 hgvs
    if ($pipeline eq 'hotspot') {
        @reason = ();
    }

    if (@reason) {
        print TAG_OUT join(";", @reason), "\t", join("\t", @line), "\n";
        next;
    }

    $line[6] = $gene;

    my $validated;
    if ($pipeline == 'somatic' || $pipeline == 'hotspot') {
        $validated = '1';
    }
    elsif ($pipeline == 'germline') {
        if ($line[16] =~ /Likely_pathogenic|drug/i) {
            $validated = '2';
        }
        elsif ($line[16] =~ /pathogenic/i and $line[16] !~ /Conflicting/i) {
            $validated = '1';
        }
        else {
            $validated = '3';
        }
    }

    my $new_line = join("\t", @line[0 .. 6], $freq, @line[7 .. 20, 23, 28, 32, 50, 56, 62, 101, 102], $pipeline);
    print OUT "$validated\t$new_line\n";
    print TAG_OUT "PASS\t$new_line\n";
}

# black list
sub blacklist {
    my $public_path = defined $ENV{'PUBLIC'} ? $ENV{'PUBLIC'} : "/dataseq/jmdna/codes/public/";
    open BKLT, "$public_path/blacklist.txt";
    my %bk;
    <BKLS>;
    while (<BKLT>) {
        chomp;
        my @line = split("\t");
        my $key = join("_", @line[0 .. 4]);
        $bk{$key} = 1;
    }
    return \%bk;
}

sub mut_gene {
    my $public_path = defined $ENV{'PUBLIC'} ? $ENV{'PUBLIC'} : "/dataseq/jmdna/codes/public/";
    open INFO, "$public_path/info.csv";
    my @muts;
    while (<INFO>) {
        chomp;
        my @line = split(/,/, $_);
        if ($line[0] eq $project) {
            if (($line[2] ne "NA") and ($line[9] ne "NA")) {
                @muts = split(/\//, $line[2]);
                last;
            }
        }
    }
    return @muts
}

sub transcript {
    my $database_path = defined $ENV{'DATABASE'} ? $ENV{'DATABASE'} : "/dataseq/jmdna/codes/reportbase/";
    open TR, "$database_path/oncokbgene.txt";
    my %oncogene;
    while (<TR>) {
        chomp;
        my @line = split;
        $oncogene{$line[0]} = $line[2];
        $oncogene{$line[0]} =~ s/\.\d+//;
    }
    return %oncogene;
}