Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000488916 | SCV000576760 | uncertain significance | not provided | 2017-04-20 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the NIPBL gene. The c.5843 T>A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.5843 T>A variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Several in-silico splice prediction models predict that c.5843 T>A creates a cryptic donor site in exon 32 which may lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. If the c.5843 T>A variant does not affect splicing, it will result in the F1948Y missense change. The F1948Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with NIPBL-related disorders (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. |