Journal
NUCLEIC ACIDS RESEARCH
Volume 46, Issue 15, Pages 7913-7923Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gky372
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Funding
- NHMRC [1061779]
- Cancer Council Queensland [1086286]
- French National Cancer Institute Translational Research Grant
- Direction Generale de l'Offre des Soins (INCa/DGOS)
- Laboratoire de Biologie et Genetique du Cancer
- Centre Francois Baclesse, Caen, France
- National Health and Medical Research Council of Australia [1061779] Funding Source: NHMRC
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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 fromSpliceSiteFinder-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 of variants in the next-generation sequencing era. SPiCE is accessible at (https://sourceforge.net/projects/spicev2-1/).
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