AmazonForest: In Silico Metaprediction of Pathogenic Variants

SIMPLE SUMMARY: ClinVar is a valuable platform that stores a large set of relevant genetic associations with complex phenotypes. However, the functional impact of a partial set of such associations remains misinterpreted, due to the presence of variants with uncertain significance or with conflicting pathogenicity interpretations. To fill this gap, we present AmazonForest: a metaprediction model based on Random Forest for pathogenicity prediction. AmazonForest was used to reclassify a set of ∼101,000 variants that were predicted as having high pathogenic probability. AmazonForest is available as a web tool with a simple web interface, and also as an R object for pathogenicity predictions. ABSTRACT: ClinVar is a web platform that stores ∼789,000 genetic associations with complex diseases. A partial set of these cataloged genetic associations has challenged clinicians and geneticists, often leading to conflicting interpretations or uncertain clinical impact significance. In this study, we addressed the (re)classification of genetic variants by AmazonForest, which is a random-forest-based pathogenicity metaprediction model that works by combining functional impact data from eight prediction tools. We evaluated the performance of representation learning algorithms such as autoencoders to propose a better strategy. All metaprediction models were trained with ClinVar data, and genetic variants were annotated with eight functional impact predictors cataloged with SnpEff/SnpSift. AmazonForest implements the best random forest model with a one hot data-encoding strategy, which shows an Area Under ROC Curve of ≥0.93. AmazonForest was employed for pathogenicity prediction of a set of ∼101,000 genetic variants of uncertain significance or conflict of interpretation. Our findings revealed ∼24,000 variants with high pathogenic probability ([Formula: see text]). In addition, we show results for Alzheimer’s Disease as a demonstration of its application in clinical interpretation of genetic variants in complex diseases. Lastly, AmazonForest is available as a web tool and R object that can be loaded to perform pathogenicity predictions.