Hi all,

I am using Ensembl VEP (command line) to annotate a VCF I have. I am specifically looking for gnomAD allele frequencies, which is fairly straight forward to do, technically speaking. However, the data looks off in some cases.

For example, when I pass in:

    10	69408929	COSM3751912	A	T	.	.	GENE=TACR2;STRAND=-;CDS=c.734T>A;AA=p.M245K

I get the VEP output:

    COSM3751912	10:69408929	T	ENSG00000075073	ENST00000373306	Transcript	missense_variant	1278	734	245	M/K	aTg/aAg	rs55953810	MODERATE	-	-1	-	TACR2	HGNC	HGNC:11527	YES	ENSP00000362403	P21452	-	UPI0000061EE3	-	3/5	-	Gene3D:1.20.1070.10,Pfam_domain:PF00001,PROSITE_profiles:PS50262,hmmpanther:PTHR43919,hmmpanther:PTHR43919:SF4,SMART_domains:SM01381,Superfamily_domains:SSF81321,Conserved_Domains:cd16004	1	1	1	1	1	0.9999	0.9999	0.9999	1	0.9999	1	0.9999	1	1	1	gnomAD_ASJ,gnomAD_FIN,gnomAD_OTH,gnomAD_SAS,AFR,AMR,EAS,EUR,SAS	-	-	-	-	-	-	-

Jumbling through that, you can see the allele frequencies for `gnomAD_AF` is **0.9999**. This seems odd to me. How could this variant be a COSMIC (cancer database) missense variant, with `MODERATE` consequence, and have **99.99%** frequency. I'm lost on how to interpret this.

Maybe I am misunderstanding how gnomAD scores allele frequencies, hence posting this question here.

**Does anyone know how gnomAD allele frequencies (as outputted by Ensembl's VEP) should be interpreted?**
The reference allele, in this case, appears to be a very rare allele. The reference allele is whatever was found in the reference genome, which is a genomic region of a real person, which means that it can be a rare or private allele. In this case, the reference, A, is very rare.

The VEP is giving you the allele frequency of the alternative allele for the variant at this locus, which is [rs55953810](http://www.ensembl.org/Homo_sapiens/Variation/Population?db=core;r=10:69408429-69409429;tl=2uCd0VOAH86sXHFW-4871232;v=rs55953810;vdb=variation;vf=73998235). The alternative allele given in your VEP input is T, so the allele frequency it gives you is for T.

VEP reads VCF format as standard, assuming that the alleles are the forward strand alleles. Your specification of strand in the INFO column is ignored because this is not the standard way to write VCF. This is why your alleles have not been converted.

It appears that you have run your VEP input against GRCh38. gnomAD coordinates are on GRCh37, and are remapped onto GRCh38, so can be looked up by the VEP to find the allele frequencies. This is why there is no variant at that locus in gnomAD, but [that variant identifier and its frequencies do exist](http://gnomad.broadinstitute.org/variant/10-71168685-A-T).