Guidance for clinical variant classification in genes for spliceosomal small nuclear RNAs

Small nuclear RNAs (snRNAs) are RNA components of spliceosomes that play a key role in splice-site recognition and control of the RNA splicing process. Variants in genes producing snRNAs are increasingly recognized as major contributors to rare disorders, including neurodevelopmental disorders and retinal dystrophies. A research team analyzed de novo variants from 12,007 trios and found approximately a 50-fold increase in de novo mutation rate in snRNA genes compared to intergenic sequences. Classification of variants in snRNA genes is challenging due to difficulties in variant identification, the high number of gene paralogs with similar sequences, and historical inaccuracies in snRNA gene annotation. An expert panel developed the first specific recommendations for classifying variants in snRNA genes and introduced RNUdb, an interactive web-based tool to support snRNA variant annotation and classification.