Consequence calling

The BCFtools/csq command is a very fast program for haplotype-aware consequence calling which can take into account known phase. It avoids the common pitfall of existing predictors which analyze variants as isolated events and correctly predicts consequences for adjacent variants which alter the same codon or frame-shifting indels followed by a frame-restoring indels.

Three types of compound variants that lead to incorrect consequence prediction when handled in a localized manner each separately rather than jointly.
A) Multiple SNVs in the same codon result in a TAG stop codon rather than an amino acid change. B) A deletion locally predicted as frame-shifting is followed by a frame-restoring variant. Two amino acids are deleted and one changed, the functional consequence on protein function is likely much less severe. C) Two SNVs separated by an intron occur within the same codon in the spliced transcript.
Unchanged areas are shaded for readability. All three examples were encountered in real data.

The program requires on input a VCF/BCF file, the reference genome in fasta format and genomic features in the GFF3 format downloadable from the Ensembl website, and outputs an annotated VCF/BCF file. Currently, only Ensembl GFF3 files are supported, see for example ftp://ftp.ensembl.org/pub/current_gff3/homo_sapiens.

The typical command looks like this

bcftools csq -f hs37d5.fa -g Homo_sapiens.GRCh37.82.gff3.gz in.vcf -Ob -o out.bcf

For more details please see the manual page.

References

Please cite this paper if you find our software useful: http://biorxiv.org/content/early/2016/12/01/090811

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