For a variant with MAF < 0.5% that is absent from both ClinVar and HGMD, the DVD relies on functional prediction annotations to classify the variant as either LB or VUS (Figure 1). Our pipeline currently supports two evolutionary conservation algorithms (phyloP17 and GERP++18) and four deleteriousness prediction algorithms (SIFT,19 PolyPhen-2,20 MutationTaster,21 and LRT22). The DVD calculates a composite pathogenicity score (PS), assigning 1 point for each conserved and damaging prediction to make a final prediction of either VUS or LB. When multiple scores for the same prediction or conservation algorithm are provided, DVD selects the most damaging prediction from the set to consider in its algorithms. The LB classification is warranted if a variant has ≤40% pathogenic predictions and at least 5 algorithms make a prediction. In all other instances, the variant is computationally classified as a VUS (Figure 1C).