What question did this study set out to answer?

To assess the prevalence, classification, and disease associations of splicing variants across large datasets and quantify how RNA analysis can resolve variants of uncertain significance.

March 19, 2021The American Journal of Human GeneticsOpen Access

Spectrum of splicing variants in disease genes and the ability of RNA analysis to reduce uncertainty in clinical interpretation

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Authors

RTRebecca TrutyInvitae (United States)KOKaren OuyangUniversity of California, Los Angeles SRSusan RojahnNatera (United States)

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Implication

Cohort study reveals splicing variants occur in 5.4% of clinical patients, indicating RNA analysis can resolve ambiguous variants primarily toward benign status.

Key Points

To assess the prevalence, classification, and disease associations of splicing variants across large datasets and quantify how RNA analysis can resolve variants of uncertain significance.
Analyzed genomic and classification data across a clinical cohort of N=689,321 individuals alongside two public databases (ClinVar and gnomAD).
Modeled the clinical diagnostic impact of incorporating RNA analysis as supporting functional evidence for reclassifying splicing variants of uncertain significance.
Splicing variants comprised 13% of all pathogenic, likely pathogenic, or uncertain variants in the clinical cohort, with 5.4% of tested individuals harboring a splicing variant of uncertain significance.
RNA analysis was estimated to reclassify splicing variants of uncertain significance in 1.7% of cohort individuals, producing a pathogenic or likely pathogenic result in 0.1% while reclassifying most to likely benign.
Splicing variants made up 4.8% of variants in ClinVar and 9.4% of protein-coding variants in gnomAD, exhibiting depletion in genes linked to haploinsufficiency and dominant inheritance.

Cite This Study

Truty et al. (2021) studied this question.

synapsesocial.com/papers/6aad098cf627e811e2dc07b1 https://doi.org/10.1016/j.ajhg.2021.03.006

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Implication

Cohort study reveals splicing variants occur in 5.4% of clinical patients, indicating RNA analysis can resolve ambiguous variants primarily toward benign status.

Spectrum of splicing variants in disease genes and the ability of RNA analysis to reduce uncertainty in clinical interpretation

Discussion

Member takes

Implication

Key Points

Cite This Study

Spectrum of splicing variants in disease genes and the ability of RNA analysis to reduce uncertainty in clinical interpretation

Discussion

Member takes

Implication

Key Points

Cite This Study

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