MAF Thresholds for Disease-Causing Variants Are Gene Specific
Gene-specific MAF thresholds for P+LP variants ranged from 0% to 7.34%. GJB2, MYO15A, OTOF (MIM: 603681), PEX6 (MIM: 601498), and CLRN1 (MIM: 601498) had the highest MAFs at 7.34%, 2.45%, 0.79%, 0.71%, and 0.69%, respectively (Table S6). However, these maximum MAFs are misleading and do not provide an accurate MAF for the majority of disease-causing variants associated with these genes. For example, while the maximum MAF for any pathogenic variant reported in GJB2 (GenBank: NM_004004.5) is 7.3% for c.109G>A (p.Val37Ile), the median MAF for all mutations in GJB2 is surprisingly 0, reflecting the huge number of ultra-rare P+LP variants in this gene (Figures 6A, 6B, and S5, Table S6). Similar results were found for SLC26A4, USH2A, and WFS1. These discrepancies also reflect founder effects as some mutations occur solely in a single population or ethnicity and account for a large portion of that population’s hearing loss (Table S2). These critical exceptions emphasize the importance of expert curation and review of variants that exceed the 0.5% MAF cut-off.
Figure 6 MAFs Thresholds for Deafness-Associated Variants Are Gene and Type Specific
(A) Plot of MAFs of all P/LP variants in each deafness-associated gene.
(B) Maximum MAF is gene specific and there is a clear distinction between LoF versus missense variants.
(C) Overall, missense variants exhibit the highest MAFs when compared to all other variants.
Only genes with ≥14 reported deafness-associated variants are included in this figure; the remaining genes are shown in Figure S5.