Novel diagnostic tool for prediction of variant spliceogenicity derived from a set of 395 combined in silico/in vitro studies: an international collaborative effort

Nucleic Acids Research
Raphaël LemanClaude Houdayer

Abstract

Variant interpretation is the key issue in molecular diagnosis. Spliceogenic variants exemplify this issue as each nucleotide variant can be deleterious via disruption or creation of splice site consensus sequences. Consequently, reliable in silico prediction of variant spliceogenicity would be a major improvement. Thanks to an international effort, a set of 395 variants studied at the mRNA level and occurring in 5' and 3' consensus regions (defined as the 11 and 14 bases surrounding the exon/intron junction, respectively) was collected for 11 different genes, including BRCA1, BRCA2, CFTR and RHD, and used to train and validate a new prediction protocol named Splicing Prediction in Consensus Elements (SPiCE). SPiCE combines in silico predictions from SpliceSiteFinder-like and MaxEntScan and uses logistic regression to define optimal decision thresholds. It revealed an unprecedented sensitivity and specificity of 99.5 and 95.2%, respectively, and the impact on splicing was correctly predicted for 98.8% of variants. We therefore propose SPiCE as the new tool for predicting variant spliceogenicity. It could be easily implemented in any diagnostic laboratory as a routine decision making tool to help geneticists to face the deluge o...Continue Reading

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Citations

Jan 23, 2020·American Journal of Medical Genetics. Part C, Seminars in Medical Genetics·Geoffroy DelplancqPaul Kuentz
Apr 1, 2020·International Journal of Molecular Sciences·Mubeen KhanFrans P M Cremers
Jun 3, 2020·International Journal of Molecular Sciences·Elizabeth Santana Dos SantosEtienne Rouleau
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May 24, 2020·Nature Communications·Masachika IkegamiHiroyuki Mano
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Apr 16, 2021·Clinica Chimica Acta; International Journal of Clinical Chemistry·Abdellah TebaniSoumeya Bekri
May 25, 2021·Leukemia & Lymphoma·Cosimo CumboFrancesco Albano
Jun 29, 2021·Frontiers in Molecular Biosciences·Jan ZrimecAleksej Zelezniak
Jul 11, 2021·Journal of Human Genetics·Jessie PoquérusseJessie C Jacobsen

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Software Mentioned

R package ROCR
SSF
NNS
like
Splice Site Finder
Alamut
Splicing Predictions in Consensus Elements ( SPiCE )
Interactive Biosoftware
Alamut Visual
SPiCE

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