Fig. 3

Performance of computational methods in correctly identifying pathogenic variants in the two principal rare disease variant databases, HGMD and ClinVar. The left panels show data for variants labeled as “pathogenetic” in ClinVar and “DM” in HGMD together with “benign” in ClinVar. The right panels add variants labeled as “likely pathogenic” and “likely benign” in ClinVar as well as “DM?” in HGMD. Meta and single method examples were selected on the basis of the average ranking of each method for the ROC and truncated ROC AUCs. See Additional file 1 for more details and selection criteria. A ROC curves for the selected metapredictors and single methods, together with a baseline provided by PolyPhen-2. Particularly for pathogenic variants alone, impressively high ROC areas are obtained, above 0.9, and there is a substantial improvement over the older method’s performance. B Blowup of the left-hand portion of the ROC curves, most relevant to high confident identification of pathogenic variants. Clinical thresholds for Supporting, Moderate, and Strong clinical evidence are shown. C Local positive likelihood ratio as a function of the confidence score returned by REVEL. Very high values (> 100) are obtained for the most confident pathogenic assignments. D Local posterior probability of pathogenicity; that is, probability that a variant is pathogenic as a function of the REVEL score for the two prior probability scenarios. For a prior probability of 0.1, typical of a single candidate gene situation (solid line) and database pathogenic and benign variants (left panel) the highest-scoring variants reach posterior probability above 0.9, strong enough evidence for a clinical assignment of “likely pathogenic.” In both panels, variants with a score greater than 0.45 provide Supporting clinical evidence (green threshold), and scores greater than 0.8 provide Strong evidence (red threshold). The estimated % of variants encountered in a clinical setting expected to meet each threshold are also shown. For example, about 14% of variants provide Supporting evidence. Dotted lines show results obtained with a prior probability of 0.01