An expanded phenotype centric benchmark of variant prioritisation tools

Abstract

Identifying the causal variant for diagnosis of genetic diseases is challenging when using next-generation sequencing approaches and variant prioritization tools can assist in this task. These tools provide in silico predictions of variant pathogenicity, however they are agnostic to the disease under study. We previously performed a disease-specific benchmark of 24 such tools to assess how they perform in different disease contexts. We found that the tools themselves show large differences in performance, but more importantly that the best tools for variant prioritization are dependent on the disease phenotypes being considered. Here we expand the assessment to 37 tools and refine our assessment by separating performance for nonsynonymous single nucleotide variants (nsSNVs) and missense variants (i.e., excluding nonsense variants). We found differences in performance for missense variants compared to nsSNVs and recommend three tools that stand out in terms of their performance (BayesDel, CADD, and ClinPred).

Keywords: dbNSFP; disease; human phenotype ontology; phenotype; variant prioritization.

Figure 1

Heatmaps showing performance (auPRC) of variant prioritization tools for missense variants (a) and nsSNVs (b). Color coding of columns is based on the method used to predict pathogenicity, where black = conservation scores, yellow = machine learning scores and red = ensemble scores. Hierarchical cluster analysis with Euclidean distance and complete agglomeration was used to cluster both the tools and the HPO terms. HPO, Human Phenotype Ontology

Figure 2

Boxplots showing auPRC of the top performing variant prioritization tools across selected top level HPO phenotypic abnormality terms and all their descendant terms for missense variants and nsSNVs. Abnormality of metabolism/homeostasis includes 340 terms for missense variants and 443 for nsSNVs. Abnormality of the immune system includes 242 terms for missense variants and 288 for nsSNVs. Abnormality of the nervous system includes 806 terms for missense variants and 898 for nsSNVs. Neoplasm includes 227 terms for missense variants and 291 for nsSNVs. auPRC, area under the precision‐recall curve; nsSNV, nonsynonymous single nucleotide variant