Spectrum of splicing variants in disease genes and the ability of RNA analysis to reduce uncertainty in clinical interpretation.
RNA analysis
functional studies
gene panel
genetic testing
in silico prediction
next-generation sequencing
splice site
splicing
variant classification
variants of uncertain significance
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
01 04 2021
01 04 2021
Historique:
received:
10
11
2020
accepted:
02
03
2021
pubmed:
21
3
2021
medline:
8
5
2021
entrez:
20
3
2021
Statut:
ppublish
Résumé
The complexities of gene expression pose challenges for the clinical interpretation of splicing variants. To better understand splicing variants and their contribution to hereditary disease, we evaluated their prevalence, clinical classifications, and associations with diseases, inheritance, and functional characteristics in a 689,321-person clinical cohort and two large public datasets. In the clinical cohort, splicing variants represented 13% of all variants classified as pathogenic (P), likely pathogenic (LP), or variants of uncertain significance (VUSs). Most splicing variants were outside essential splice sites and were classified as VUSs. Among all individuals tested, 5.4% had a splicing VUS. If RNA analysis were to contribute supporting evidence to variant interpretation, we estimated that splicing VUSs would be reclassified in 1.7% of individuals in our cohort. This would result in a clinically significant result (i.e., P/LP) in 0.1% of individuals overall because most reclassifications would change VUSs to likely benign. In ClinVar, splicing VUSs were 4.8% of reported variants and could benefit from RNA analysis. In the Genome Aggregation Database (gnomAD), splicing variants comprised 9.4% of variants in protein-coding genes; most were rare, precluding unambiguous classification as benign. Splicing variants were depleted in genes associated with dominant inheritance and haploinsufficiency, although some genes had rare variants at essential splice sites or had common splicing variants that were most likely compatible with normal gene function. Overall, we describe the contribution of splicing variants to hereditary disease, the potential utility of RNA analysis for reclassifying splicing VUSs, and how natural variation may confound clinical interpretation of splicing variants.
Identifiants
pubmed: 33743207
pii: S0002-9297(21)00090-2
doi: 10.1016/j.ajhg.2021.03.006
pmc: PMC8059334
pii:
doi:
Substances chimiques
RNA Splice Sites
0
RNA
63231-63-0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
696-708Informations de copyright
Copyright © 2021 Invitae Corporation. Published by Elsevier Inc. All rights reserved.
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