Assessing computational predictions of the phenotypic effect of cystathionine-beta-synthase variants

Laura Kasak, Constantina Bakolitsa, Zhiqiang Hu, Changhua Yu, Jasper Rine, Dago F. Dimster-Denk, Gaurav Pandey, Greet De Baets, Yana Bromberg, Chen Cao, Emidio Capriotti, Rita Casadio, Joost Van Durme, Manuel Giollo, Rachel Karchin, Panagiotis Katsonis, Emanuela Leonardi, Olivier Lichtarge, Pier Luigi Martelli, David MasicaSean D. Mooney, Ayodeji Olatubosun, Predrag Radivojac, Frederic Rousseau, Lipika R. Pal, Castrense Savojardo, Joost Schymkowitz, Janita Thusberg, Silvio C.E. Tosatto, Mauno Vihinen, Jouni Väliaho, Susanna Repo, John Moult, Steven E. Brenner, Iddo Friedberg

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


Accurate prediction of the impact of genomic variation on phenotype is a major goal of computational biology and an important contributor to personalized medicine. Computational predictions can lead to a better understanding of the mechanisms underlying genetic diseases, including cancer, but their adoption requires thorough and unbiased assessment. Cystathionine-beta-synthase (CBS) is an enzyme that catalyzes the first step of the transsulfuration pathway, from homocysteine to cystathionine, and in which variations are associated with human hyperhomocysteinemia and homocystinuria. We have created a computational challenge under the CAGI framework to evaluate how well different methods can predict the phenotypic effect(s) of CBS single amino acid substitutions using a blinded experimental data set. CAGI participants were asked to predict yeast growth based on the identity of the mutations. The performance of the methods was evaluated using several metrics. The CBS challenge highlighted the difficulty of predicting the phenotype of an ex vivo system in a model organism when classification models were trained on human disease data. We also discuss the variations in difficulty of prediction for known benign and deleterious variants, as well as identify methodological and experimental constraints with lessons to be learned for future challenges.

Original languageEnglish
Pages (from-to)1530-1545
Number of pages16
JournalHuman Mutation
Issue number9
StatePublished - 1 Sep 2019
Externally publishedYes


  • CAGI challenge
  • critical assessment
  • cystathionine-beta-synthase
  • machine learning
  • phenotype prediction
  • single amino acid substitution


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