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Official code repository for GATK versions 4 and up
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Funcotator - Problems with variant alleles that span exon, coding sequence start/end boundaries #4307

Open jonn-smith opened 6 years ago

jonn-smith commented 6 years ago

The way start positions are calculated causes issues when alleles span the boundaries of exons and the coding sequence itself.

For exon boundaries:

The error stems from FuncotatorUtils::getStartPositionInCodingSequence and how the results of that method call are used in the GencodeFuncotationFactory.

In addition: Funcotator must be able to handle indels that span exon start boundaries.

For example, in hg19 the following variant is not handled properly:

chr5:71622537-71622538 CA->C

The current workaround is to throw a FuncotatorUtils.TranscriptCodingSequenceException for the transcript causing this problem in Gencode.

For Coding sequence boundaries, the following variant in hg38 causes a problem:

chr17 80090386  rs71163918  CAGCACGTGCATGAACAACACAGGACACACACAGCACGTGCATGAACAACACAGGACACACACA  C . PASS  .
jonn-smith commented 6 years ago

A temporary fix is in that will only annotate variants as in a CDS if they are contained within that CDS.

jonn-smith commented 6 years ago

This is related to #4804

jonn-smith commented 6 years ago

Can oncotator handle this?

jonn-smith commented 6 years ago

Funcotator and Oncotator both produce the same results for chr5:71622537-71622538 CA->C. They both seem to ignore the transcript that runs off the end of the boundary.

jonn-smith commented 5 years ago

GencodeFuncotationFactory::getContainingGtfSubfeature contains a "fix" to get around this issue.

jonn-smith commented 5 years ago

This is related to #3749

jonn-smith commented 5 years ago

For the following variants:

chr1 819955 . TTCACGAATT T . PASS . chr1 819979 . CATGAGCAT C . PASS .

VEP seems to produce incorrect data: 

##fileformat=VCFv4.1
##VEP="v94" time="2018-10-30 19:13:50" cache="/nfs/public/release/ensweb-data/latest/tools/grch37/e94/vep/cache/homo_sapiens/94_GRCh37" db="homo_sapiens_core_94_37@hh-mysql-ens-grch37-web" 1000genomes="phase3" COSMIC="81" ClinVar="201706" ESP="20141103" HGMD-PUBLIC="20164" assembly="GRCh37.p13" dbSNP="150" gencode="GENCODE 19" genebuild="2011-04" gnomAD="170228" polyphen="2.2.2" regbuild="1.0" sift="sift5.2.2"
##INFO=<ID=CSQ,Number=.,Type=String,Description="Consequence annotations from Ensembl VEP. Format: Allele|Consequence|IMPACT|SYMBOL|Gene|Feature_type|Feature|BIOTYPE|EXON|INTRON|HGVSc|HGVSp|cDNA_position|CDS_position|Protein_position|Amino_acids|Codons|Existing_variation|DISTANCE|STRAND|FLAGS|SYMBOL_SOURCE|HGNC_ID|TSL|APPRIS|ENSP|SIFT|PolyPhen|AF|AFR_AF|AMR_AF|EAS_AF|EUR_AF|SAS_AF|AA_AF|EA_AF|gnomAD_AF|gnomAD_AFR_AF|gnomAD_AMR_AF|gnomAD_ASJ_AF|gnomAD_EAS_AF|gnomAD_FIN_AF|gnomAD_NFE_AF|gnomAD_OTH_AF|gnomAD_SAS_AF|CLIN_SIG|SOMATIC|PHENO|PUBMED|MOTIF_NAME|MOTIF_POS|HIGH_INF_POS|MOTIF_SCORE_CHANGE">
#CHROM  POS ID  REF ALT QUAL    FILTER  INFO
chr1    819955  .   TTCACGAATT  T   .   PASS    CSQ=-|splice_acceptor_variant&coding_sequence_variant&intron_variant|HIGH|AL645608.2|ENSG00000269308|Transcript|ENST00000594233|protein_coding|3/3|2/2|||?-38|?-38|?-13|||||1||Clone_based_ensembl_gene||||ENSP00000470877|||||||||||||||||||||||||||
chr1    819979  .   CATGAGCAT   C   .   PASS    CSQ=-|coding_sequence_variant&3_prime_UTR_variant|MODIFIER|AL645608.2|ENSG00000269308|Transcript|ENST00000594233|protein_coding|3/3||||54-?|54-?|18-?|||||1||Clone_based_ensembl_gene||||ENSP00000470877|||||||||||||||||||||||||||

There is no cDNA string / amino acid change and the positions have ? characters in them (not 100% sure the question marks are wrong - there is no real spec for these fields).

Oncotator seems to produce incorrect data:

##fileformat=VCFv4.1
##fileDate=Thu Sept 6 15:53:20 UTC 2018
##reference=/cromwell_root/broad-references/hg19/v0/Homo_sapiens_assembly19.fasta
##oncotator_version=Oncotator_v1.10.0.0dev_|_Flat_File_Reference_hg19_|_GENCODE_v19_CANONICAL_
##INFO=<ID=annotation_transcript,Number=.,Type=String,Description="Unknown">
##INFO=<ID=gencode_transcript_status,Number=.,Type=String,Description="Unknown">
##INFO=<ID=HGVS_protein_change,Number=.,Type=String,Description="Unknown">
##INFO=<ID=genome_change,Number=.,Type=String,Description="Unknown">
##INFO=<ID=ccds_id,Number=.,Type=String,Description="Unknown">
##INFO=<ID=codon_change,Number=.,Type=String,Description="Unknown">
##INFO=<ID=HGVS_coding_DNA_change,Number=.,Type=String,Description="Unknown">
##INFO=<ID=transcript_position,Number=.,Type=String,Description="Unknown">
##INFO=<ID=transcript_change,Number=.,Type=String,Description="Unknown">
##INFO=<ID=other_transcripts,Number=.,Type=String,Description="Unknown">
##INFO=<ID=HGVS_genomic_change,Number=.,Type=String,Description="Unknown">
##INFO=<ID=gencode_transcript_tags,Number=.,Type=String,Description="Unknown">
##INFO=<ID=variant_classification,Number=.,Type=String,Description="Unknown">
##INFO=<ID=secondary_variant_classification,Number=.,Type=String,Description="Unknown">
##INFO=<ID=gene_id,Number=.,Type=String,Description="Unknown">
##INFO=<ID=gencode_transcript_name,Number=.,Type=String,Description="Unknown">
##INFO=<ID=transcript_exon,Number=.,Type=String,Description="Unknown">
##INFO=<ID=havana_transcript,Number=.,Type=String,Description="Unknown">
##INFO=<ID=gene_type,Number=.,Type=String,Description="Unknown">
##INFO=<ID=gencode_transcript_type,Number=.,Type=String,Description="Unknown">
##INFO=<ID=protein_change,Number=.,Type=String,Description="Unknown">
##INFO=<ID=ref_context,Number=.,Type=String,Description="Unknown">
##INFO=<ID=variant_type,Number=.,Type=String,Description="Unknown">
##INFO=<ID=transcript_id,Number=.,Type=String,Description="Unknown">
##INFO=<ID=gc_content,Number=.,Type=String,Description="Unknown">
##INFO=<ID=gene,Number=.,Type=String,Description="Unknown">
##INFO=<ID=transcript_strand,Number=.,Type=String,Description="Unknown">
##FORMAT=<ID=GT,Number=1,Type=String,Description="Genotype">
##contig=<ID=1,length=249250621>
##contig=<ID=2,length=243199373>
##contig=<ID=3,length=198022430>
##contig=<ID=4,length=191154276>
##contig=<ID=5,length=180915260>
##contig=<ID=6,length=171115067>
##contig=<ID=7,length=159138663>
##contig=<ID=8,length=146364022>
##contig=<ID=9,length=141213431>
##contig=<ID=10,length=135534747>
##contig=<ID=11,length=135006516>
##contig=<ID=12,length=133851895>
##contig=<ID=13,length=115169878>
##contig=<ID=14,length=107349540>
##contig=<ID=15,length=102531392>
##contig=<ID=16,length=90354753>
##contig=<ID=17,length=81195210>
##contig=<ID=18,length=78077248>
##contig=<ID=19,length=59128983>
##contig=<ID=20,length=63025520>
##contig=<ID=21,length=48129895>
##contig=<ID=22,length=51304566>
##contig=<ID=X,length=155270560>
##contig=<ID=Y,length=59373566>
##contig=<ID=MT,length=16569>
##contig=<ID=GL000207.1,length=4262>
##contig=<ID=GL000226.1,length=15008>
##contig=<ID=GL000229.1,length=19913>
##contig=<ID=GL000231.1,length=27386>
##contig=<ID=GL000210.1,length=27682>
##contig=<ID=GL000239.1,length=33824>
##contig=<ID=GL000235.1,length=34474>
##contig=<ID=GL000201.1,length=36148>
##contig=<ID=GL000247.1,length=36422>
##contig=<ID=GL000245.1,length=36651>
##contig=<ID=GL000197.1,length=37175>
##contig=<ID=GL000203.1,length=37498>
##contig=<ID=GL000246.1,length=38154>
##contig=<ID=GL000249.1,length=38502>
##contig=<ID=GL000196.1,length=38914>
##contig=<ID=GL000248.1,length=39786>
##contig=<ID=GL000244.1,length=39929>
##contig=<ID=GL000238.1,length=39939>
##contig=<ID=GL000202.1,length=40103>
##contig=<ID=GL000234.1,length=40531>
##contig=<ID=GL000232.1,length=40652>
##contig=<ID=GL000206.1,length=41001>
##contig=<ID=GL000240.1,length=41933>
##contig=<ID=GL000236.1,length=41934>
##contig=<ID=GL000241.1,length=42152>
##contig=<ID=GL000243.1,length=43341>
##contig=<ID=GL000242.1,length=43523>
##contig=<ID=GL000230.1,length=43691>
##contig=<ID=GL000237.1,length=45867>
##contig=<ID=GL000233.1,length=45941>
##contig=<ID=GL000204.1,length=81310>
##contig=<ID=GL000198.1,length=90085>
##contig=<ID=GL000208.1,length=92689>
##contig=<ID=GL000191.1,length=106433>
##contig=<ID=GL000227.1,length=128374>
##contig=<ID=GL000228.1,length=129120>
##contig=<ID=GL000214.1,length=137718>
##contig=<ID=GL000221.1,length=155397>
##contig=<ID=GL000209.1,length=159169>
##contig=<ID=GL000218.1,length=161147>
##contig=<ID=GL000220.1,length=161802>
##contig=<ID=GL000213.1,length=164239>
##contig=<ID=GL000211.1,length=166566>
##contig=<ID=GL000199.1,length=169874>
##contig=<ID=GL000217.1,length=172149>
##contig=<ID=GL000216.1,length=172294>
##contig=<ID=GL000215.1,length=172545>
##contig=<ID=GL000205.1,length=174588>
##contig=<ID=GL000219.1,length=179198>
##contig=<ID=GL000224.1,length=179693>
##contig=<ID=GL000223.1,length=180455>
##contig=<ID=GL000195.1,length=182896>
##contig=<ID=GL000212.1,length=186858>
##contig=<ID=GL000222.1,length=186861>
##contig=<ID=GL000200.1,length=187035>
##contig=<ID=GL000193.1,length=189789>
##contig=<ID=GL000194.1,length=191469>
##contig=<ID=GL000225.1,length=211173>
##contig=<ID=GL000192.1,length=547496>
##contig=<ID=NC_007605,length=171823>
#CHROM  POS ID  REF ALT QUAL    FILTER  INFO
1   819955  .   TTCACGAATT  T   .   PASS    annotation_transcript=ENST00000594233.1;gencode_transcript_status=NOVEL;genome_change=g.chr1:819956_819964delTCACGAATT;codon_change=c.(34-39)tcacga>a;HGVS_coding_DNA_change=ENST00000594233.1:c.35-1TCACGAATT>-;transcript_position=34_38;transcript_change=c.34_38delTCACGAATT;HGVS_genomic_change=chr1.hg19:g.819956_819964delTCACGAATT;gencode_transcript_tags=basic|appris_principal;variant_classification=Splice_Site;secondary_variant_classification=In_Frame_Del;gencode_transcript_name=AL645608.2-201;transcript_exon=3;gene_type=protein_coding;gencode_transcript_type=protein_coding;protein_change=p.SR12del;ref_context=atggctattttcacgaattaattcttccg;variant_type=DEL;transcript_id=ENST00000594233.1;gc_content=0.349;gene=AL645608.2;transcript_strand=+
1   819979  .   CATGAGCAT   C   .   PASS    annotation_transcript=ENST00000594233.1;gencode_transcript_status=NOVEL;HGVS_protein_change=Exception_encountered;genome_change=g.chr1:819980_819987delATGAGCAT;HGVS_coding_DNA_change=ENST00000594233.1:c.54_*4delATGAGCAT;transcript_position=54_57;HGVS_genomic_change=chr1.hg19:g.819980_819987delATGAGCAT;gencode_transcript_tags=basic|appris_principal;variant_classification=Stop_Codon_Del;gencode_transcript_name=AL645608.2-201;transcript_exon=0;gene_type=protein_coding;gencode_transcript_type=protein_coding;ref_context=ttccgtatccatgagcatggaatgcttc;variant_type=DEL;transcript_id=ENST00000594233.1;gc_content=0.370;gene=AL645608.2;transcript_strand=+

The protein change / cdna string / coding string fields are all incorrect. The positions in the transcript may also be incorrect.

droazen commented 5 years ago

Note that this ticket also applies to variants that span between the UTR and flanking regions.