ClinVar Genomic variation as it relates to human health

This sequence change affects a donor splice site in intron 8 of the WDR34 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the WDR34 protein in which other variant(s) (p.Thr514Argfs*11) have been determined to be pathogenic (PMID: 24183451). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Disruption of this splice site has been observed in individual(s) with asphyxiating thoracic dystrophy (PMID: 24183451). This variant is present in population databases (rs371069043, gnomAD 0.003%).

Variant summary: DYNC2I2 (also known as WDR34) c.1372+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.7e-05 in 1606542 control chromosomes (gnomAD v4.0). The variant, c.1372+1G>A, has been reported in the literature in at least one individual with clinical features of Short-Rib Thoracic Dysplasia 11 With Or Without Polydactyly (Schmidts_2013). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Since the variant is located to the 5' donor site of the last intron, therefore it is not expected to elicit nonsense mediated decay (NMD). However, multiple variants downstream from this position have been reported in affected individuals (HGMD). ClinVar contains an entry for this variant (Variation ID: 2196170). Based on the evidence outlined above, the variant was classified as likely pathogenic.