RT Journal Article
SR Electronic
T1 Improving the clinical interpretation of missense variants in X linked genes using structural analysis
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 385
OP 392
DO 10.1136/jmedgenet-2020-107404
VO 59
IS 4
A1 Shalaw Rassul Sallah
A1 Jamie M Ellingford
A1 Panagiotis I Sergouniotis
A1 Simon C Ramsden
A1 Nicholas Lench
A1 Simon C Lovell
A1 Graeme C Black
YR 2022
UL http://jmg.bmj.com/content/59/4/385.abstract
AB Background Improving the clinical interpretation of missense variants can increase the diagnostic yield of genomic testing and lead to personalised management strategies. Currently, due to the imprecision of bioinformatic tools that aim to predict variant pathogenicity, their role in clinical guidelines remains limited. There is a clear need for more accurate prediction algorithms and this study aims to improve performance by harnessing structural biology insights. The focus of this work is missense variants in a subset of genes associated with X linked disorders.Methods We have developed a protein-specific variant interpreter (ProSper) that combines genetic and protein structural data. This algorithm predicts missense variant pathogenicity by applying machine learning approaches to the sequence and structural characteristics of variants.Results ProSper outperformed seven previously described tools, including meta-predictors, in correctly evaluating whether or not variants are pathogenic; this was the case for 11 of the 21 genes associated with X linked disorders that met the inclusion criteria for this study. We also determined gene-specific pathogenicity thresholds that improved the performance of VEST4, REVEL and ClinPred, the three best-performing tools out of the seven that were evaluated; this was the case in 11, 11 and 12 different genes, respectively.Conclusion ProSper can form the basis of a molecule-specific prediction tool that can be implemented into diagnostic strategies. It can allow the accurate prioritisation of missense variants associated with X linked disorders, aiding precise and timely diagnosis. In addition, we demonstrate that gene-specific pathogenicity thresholds for a range of missense prioritisation tools can lead to an increase in prediction accuracy.Some of the data that support the findings of this study are available from gnomAD, a public open access repository, at http://gnomad.broadinstitute.org. Some of the data are available from HGMD at https://portal.biobase-international.com/cgi-bin/portal/login.cgi and restrictions apply to the availability of these data, which are used under licence for this study. The rest of the data from the Manchester Genomic Diagnostic Laboratory are not publicly available due to privacy or ethical restrictions, but are available on request from the corresponding author.