[ensembl-dev] allele-specific annotation against a custom VCF

[Katherine Smith]

Dear ENSEMBL developers,

Is there any way to make VEP custom annotation against a VCF file allele-specific?

The custom annotation help page says "Users should note that the VEP will only look for overlaps (both exact and inexact) with these annotations; for example, any sequence in a GTF file will not be taken into account." (http://www.ensembl.org/info/docs/tools/vep/script/vep_custom.html)

I am using VEP 79 to annotate a VCF against allele counts from two VCF files using --custom. One VCF file is the ExAC r0.3 file (ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3/ExAC.r0.3.sites.vep.vcf.gz); this can contain multiple alternate alleles separated by a comma, e.g.

1	20395401	rs11573185	C	A,G,T	6372227.62	PASS	AC=7149,3,1

The second VCF file is 'normalised' so that a variant location with two alternate alleles is represented as two separate lines, each with only one alternate allele.

1	20395401	.	C	A	709	.	AC=2154
1	20395401	.	C	G	95	.	AC=1

I have a sample with a heterozygous C/A genotype. The INFO tag added for ExAC is "ExAC.r0.3_AC=7149,3,1", i.e. it adds the allele count for all alternate alleles, although only one is observed in this sample. The tag AC=1 is added for the other database, i.e. it adds the allele count for the G allele, which is not observed, rather than the A allele, which is.

Is there a way to make VEP only report the annotations for the alternate allele(s) observed in the input VCF?

I am running variant_effect_predictor.pl with options `--check_existing` and `--check_alleles` and custom annotation is performed using e.g. `--custom ExAC.r0.3.sites.vep.vcf.gz,ExAC.r0.3,vcf,exact,0,AF,AC,AN`

Many thanks for your advice,

Katherine