The gnomAD v2 browser announced the addition of cumulative counts of gnomAD individuals carrying pairs of rare co-occurring variants within genes, which can be used to assess how often rare variant co-occurrence is seen in a large reference population. Two variants in a gene can occur in cis or trans, and the variants can be harmful or neutral to gene function.
The differentiation between cis and trans is essential for understanding the potential of a variant pair to result in an autosomal recessive disease, which requires that both copies of a gene carry a detrimental variant.
With the availability of gnomAD v2 exome variant co-occurrence (inferred phasing) data, it is now feasible to infer phase with high confidence. The number of people carrying pairs of rare variants by inferred phase, number of alleles, and predicted functional effect is calculated for each gene. Inferred phase is determined as in trans, unphased, or in cis based on the likelihood of two variants being in trans (Ptrans). Variant pairs with Ptrans ≥ 0.55 are classified as in trans, while variant pairs with Ptrans ≤ 0.1 are classified as in cis. Unphased variant pairs are singleton-singleton variant pairs and variant pairs with indeterminate phase estimations. The thresholds for the allele frequency range from ≤ 0.5% to ≤ 5%.
The most detrimental functional impact on the canonical transcript is annotated for each variant. To improve confidence in estimated detrimental variant effects, only high-confidence predicted loss-of-function (pLoF) variants are annotated. Missense variants are classified as strong, moderate, or weak based on their REVEL score. Missense variants that are having a score of less than the weak REVEL threshold are labeled only as missense. The number of individuals carrying homozygous rare variants is presented as well.
After clicking on the “Variant co-occurrence“ tab in the gene landing page, a table with the number of individuals carrying two rare variants across the gnomAD v2 exomes (n=125,748) is presented. The table displays allele frequency thresholds of ≤ 5%, ≤ 1%, and ≤ 0.5% across six estimated functional effects. Both variants in the variant pair must have an effect that is at least as severe as the one listed. Only 32 genes have pLoF and/or strong missense variants at ≤ 1% allele frequency in trans, in contrast to 1,922 genes in cis.
A large proportion of genes with trans variants are not disease-associated in OMIM, as would be expected in a reference population devoid of severe Mendelian disease. This resource is meant to help medical genetics understand the clinical importance of rare co-occurring variants observed in patients with autosomal recessive conditions.