Fig. 1

Concept diagram for using pathogenic variant frequency distributions to establish allele frequency thresholds. Depicted is a density plot of pathogenic variants in a hypothetical gene. x-axis: allele frequency; y-axis: number of pathogenic variants. The arrows (labeled A, B, and C) highlight three different scenarios of how allele frequencies of previously uncharacterized variants can be evaluated in the context of the pathogenic variant frequency distribution. In scenario A, the uncharacterized variant has an allele frequency that is highly consistent with known pathogenic variants. Because many benign variants are also rare or private, the allele frequency of this variant provide little weight towards either classification. In scenario B, the uncharacterized variant has an allele frequency that is consistent with known pathogenic variants, but is more common than the vast majority of them. The likelihood of such a variant being pathogenic is substantially reduced. In scenario C, the uncharacterized variant has an allele frequency outside of the pathogenic variant frequency distribution. The likelihood of such a variant being pathogenic is extremely low, as it is more common than any other previously characterized pathogenic variant