ClinVar Genomic variation as it relates to human health

The BBS4 c.712-1G>A variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.712-1G>A variant has been identified in one study in which it was found in a homozygous state in one individual with Bardet-Biedl syndrome (Ellingford et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.000040 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the limited evidence and the potential impact of splice acceptor variants, the c.712-1G>A variant is classified as a variant of unknown significance but suspicious for pathogenicity for Bardet-Biedl syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

This sequence change affects an acceptor splice site in intron 10 of the BBS4 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BBS4 are known to be pathogenic (PMID: 11381270, 12016587, 20177705, 27894351). This variant is present in population databases (rs377031435, gnomAD 0.004%). Disruption of this splice site has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 27208204; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 236484). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Variant summary: BBS4 c.712-1G>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: Three predict the variant weakens the canonical 3' acceptor site and one predicts the variant abolishes the 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 251474 control chromosomes (gnomAD). c.712-1G>A has been reported in the literature in at least one homozygous individual affected with retinal disease with clinical indications of Bardet-Biedl Syndrome (Ellingford_2016). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. One laboratory classified the variant as pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.

The BBS4 c.712-1G>A variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported to be pathogenic for Bardet-Biedl syndrome (see for example, Supp. Table S5 of Ellingford et al. 2016. PubMed ID: 27208204). This variant is reported in 0.0046% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice acceptor site in BBS4 are expected to be pathogenic. This variant is interpreted as pathogenic.