Evaluating variant pathogenicity prediction tools to establish African inclusive guidelines for germline genetic...

Genetic germline testing is restricted for African patients. Lack of ancestrally relevant genomic data perpetuated by African diversity has resulted in European-biased curated clinical variant databases and pathogenic prediction guidelines. While numerous variant pathogenicity prediction tools (VPPTs) exist, their performance has yet to be established within the context of African diversity.

To address this limitation, we assessed 54 VPPTs for predictive performance (sensitivity, specificity, false positive and negative rates) across 145,291 known pathogenic or benign variants derived from 50 Southern African and 50 European men matched for advanced prostate cancer. Prioritising VPPTs for optimal ancestral performance, we screened 5.3 million variants of unknown significance for predicted functional and oncogenic potential.

We observe a 2.1- and 4.1-fold increase in the number of known and predicted rare pathogenic or benign variants, respectively, against a 1.6-fold decrease in the number of available interrogated variants in our European over African data. Although sensitivity was significantly lower for our African data overall (0.66 vs 0.71, p = 9.86E-06), MetaSVM, CADD, Eigen-raw, BayesDel-noAF, phyloP100way-vertebrate and MVP outperformed irrespective of ancestry. Conversely, MutationTaster, DANN, LRT and GERP-RS were African-specific top performers, while MutationAssessor, PROVEAN, LIST-S2 and REVEL are European-specific. Using these pathogenic prediction workflows, we narrow the ancestral gap for potentially deleterious and oncogenic variant prediction in favour of our African data by 1.15- and 1.1-fold, respectively.

Although VPPT sensitivity favours European data, our findings provide guidelines for VPPT selection to maximise rare pathogenic variant prediction for African disease studies.