VEP run with --af_gnomadg refuses to provide allele frequencies for extremely rare variants

Question

[Jeremy Leipzig]

Here are some examples. Now, I will grant you these are all extremely rare but not unknown.

HGVSg               gnomADg_AF  actual
chr20:g.63400308G>A     1.97088e-05
chr20:g.63400728C>A     1.31465e-05
chr20:g.63401127G>A     6.57263e-06
chr20:g.63402766G>A     2.6276e-05
chr20:g.63402967G>A     6.57082e-06
chr20:g.63403148G>A     1.97114e-05
chr20:g.63403351C>T     6.56927e-06
chr20:g.63403638G>A     1.31524e-05
chr20:g.63404102G>A     6.56814e-06
chr20:g.63405069C>T     6.56987e-06
chr20:g.63405079C>T     1.31409e-05
chr20:g.63405206G>A     6.57039e-06
chr20:g.63405760C>G     6.5697e-06
chr20:g.63406221C>T     6.5703e-06
chr20:g.63406556A>C     6.57073e-06

see for yourself: https://gnomad.broadinstitute.org/variant/20-63400308-G-A?dataset=gnomad_r3

[GenoMax]

Tagging: Ben_Ensembl / Louisse_Ensembl

This line serves to defeat biostars spam code.

[Louisse_Ensembl]

Hi Jeremy Leipzig,

My apologies about the delay in getting back to you. I have passed this on to my colleagues and will get back to you as soon as I have more information.

All the best,

Louisse

[Louisse_Ensembl]

Jeremy Leipzig, would you be able to share your command and tell us which assembly you are using? Thanks very much!

[Jeremy Leipzig]

the latest and greatest grch38

##VEP="v109" time="2023-07-21 01:01:24" cache="/.vep/homo_sapiens/109_GRCh38" db="[e-mail]" ensembl-funcgen=109.cba2db8 ensembl-variation=109.18a12b6 ensembl=109.10baaec ensembl-io=109.4946a86 1000genomes="phase3" COSMIC="96" ClinVar="202209" HGMD-PUBLIC="20204" assembly="GRCh38.p13" dbSNP="154" gencode="GENCODE 43" genebuild="2014-07" gnomADe="r2.1.1" gnomADg="v3.1.2" polyphen="2.2.3" regbuild="1.0" sift="6.2.1"

docker run -t -i -v $HOME/vep_data:/data ensemblorg/ensembl-vep INSTALL.pl -a cf -s homo_sapiens -y GRCh38

i this is a bit abstracted but you can assume --pick_allele was used but --mane wasn't

docker run \
        -u 1000:1000 \
        -v $HOME/vep_data:/data \
        -v $HOME/vep_data:/.vep \
        -v /home/ubuntu/rchsd-tiledb-workspace/src/rchsdtiledb/vep/variantstats2vcf:/opt/foo ensemblorg/ensembl-vep \
        vep \
        -i /opt/foo/{input} \
        -o /opt/foo/{output} \
        --cache \
        --force_overwrite \
        --fork {threads}  \
        --format vcf \
        --buffer_size 5000 \
        --terms SO \
        --symbol \
        --ccds \
        --variant_class \
        --hgvs \
        --hgvsg \
        --force \
        --dont_skip \
        --no_stats \
        {pick} \
        --vcf \
        {mane} \
        --show_ref_allele \
        --af_gnomadg

[Louisse_Ensembl]

Hi Jeremy Leipzig,

Thank you very much for your patience! It appears that the cache only contains variant information for dbSNP and certain other sources, but not gnomAD variants (we report the frequency information from gnomAD). These variants - being extremely rare - are not reported in dbSNP and other sources. A workaround is to use the --custom option to annotate your variants using gnomAD files. I hope this helps but if you have any other questions please don't hesitate to get back to me!