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Evaluating variant pathogenicity prediction tools to establish African inclusive guidelines for germline genetic testing
Zhou, K. Gheybi, K. Soh, P. X. Y. Hayes, V. M.
Zhou, K.
Gheybi, K.
Soh, P. X. Y.
Hayes, V. M.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Although VPPT sensitivity favours European data, our findings provide guidelines for VPPT selection to maximise rare pathogenic variant prediction for African disease studies.
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2025
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Zhou K, Gheybi K, Soh PXY, Hayes VM. Evaluating variant pathogenicity prediction tools to establish African inclusive guidelines for germline genetic testing. Communications medicine. 2025 May 6;5(1):157. PubMed PMID: 40328947. Pubmed Central PMCID: PMC12056225 a lack of relevant data, leading to European-biased guidelines. We address this issue by evaluating 54 variant pathogenicity prediction tools (VPPTs) using genetic data from 100 men with advanced prostate cancer, split evenly between Southern African and European ancestries. The aim is to identify which tools work best for African genetic data. While some tools performed well regardless of ancestry, others were more effective for specific populations. The study highlights the need for African-specific guidelines to improve disease prediction and health equity. The findings can help tailor genetic testing tools to better serve African populations, potentially leading to more accurate disease predictions and better health outcomes in the future. Committee and received an honorarium from the Korean Urological Oncology Society for the 2024 Annual Conference as a guest speaker. Authors K.Z., K.G. and P.X.Y.S. declare no competing interests. Epub 2025/05/07. eng.