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Comparison of predicted and actual consequences of missense mutations

2015; National Academy of Sciences; Volume: 112; Issue: 37 Linguagem: Inglês

10.1073/pnas.1511585112

1091-6490

Lisa A. Miosge, Matthew A. Field, Yovina Sontani, Vicky Cho, Simon C. Johnson, Anna Palkova, Bhavani Balakishnan, Rong Liang, Yafei Zhang, Stephen Lyon, Bruce Beutler, Belinda Whittle, Edward M. Bertram, Anselm Enders, Christopher C. Goodnow, T. Daniel Andrews,

CRISPR and Genetic Engineering

Significance Computational tools applied to any human genome sequence identify hundreds of genetic variants predicted to disrupt the function of individual proteins as the result of a single codon change. These tools have been trained on disease mutations and common polymorphisms but have yet to be tested against an unbiased spectrum of random mutations arising de novo. Here we perform such a test comparing the predicted and actual effects of de novo mutations in 23 genes with essential functions for normal immunity and all possible mutations in the TP53 tumor suppressor gene. These results highlight an important gap in our ability to relate genotype to phenotype in clinical genome sequencing: the inability to differentiate immediately clinically relevant mutations from nearly neutral mutations.