Available annotations are utilized to make an informed interpretation about the pathogenicity of each variant. MAF data from 1000 Genomes, ESP, ExAC, and our in-house database are used to determine whether a variant is too common to be considered pathogenic (Figure 1B). When considering multiple MAF annotations for a variant across databases and populations, we select the highest population-specific MAF to use in our computational evaluation. As a general rule, we use a MAF threshold of 0.5%,16 with the exception of select variants in specific genes (i.e., GJB2 [MIM: 121011]) (Table S2). A minimum of 400 alleles in the population with the highest MAF is required to use this classification threshold.