PMC:6174355 / 14818-15897 JSONTXT

{"project":"2_test","denotations":[{"id":"30245029-25262649-2047666","span":{"begin":577,"end":579},"obj":"25262649"}],"text":"All available data were used to classify variants computationally, with supplemental expert manual curation as detailed in the Material and Methods (Figure 1). We integrated predictions from six algorithms—two assessing conservation (PhyloP and GERP++) and four evaluating deleteriousness (SIFT, PolyPhen-2, MutationTaster, and LRT)—to calculate a composite pathogenicity score (PS) and annotate variants with MAF \u003c 0.5%. Variants with MAFs above this threshold were automatically classified as benign with the exception of known common founder mutations (Figure 1C, Table S2).16 To validate the PS, we plotted all variants classified as pathogenic by MAF and PS (Figure S1) and found that of 3,591 pathogenic variants with predictions from at least five pathogenicity prediction tools, 95.4% have a composite PS ≥ 60%. The calculated sensitivity, specificity, PPV, and NPV were 0.95, 0.51, 0.74, and 0.88, respectively. We used this threshold for variant classification, labeling variants with a MAF \u003c 0.5 and a PS ≤ 40%, based on at least five pathogenicity predictions, as LB."}