Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001871926 | SCV002138306 | uncertain significance | Nephronophthisis 14 | 2022-08-04 | criteria provided, single submitter | clinical testing | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1056 of the ZNF423 protein (p.Asn1056Ser). This variant is present in population databases (rs368041529, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with ZNF423-related conditions. ClinVar contains an entry for this variant (Variation ID: 1049230). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Ambry Genetics | RCV004036729 | SCV004984223 | uncertain significance | not specified | 2023-12-15 | criteria provided, single submitter | clinical testing | The c.3167A>G (p.N1056S) alteration is located in exon 5 (coding exon 4) of the ZNF423 gene. This alteration results from a A to G substitution at nucleotide position 3167, causing the asparagine (N) at amino acid position 1056 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |
| Department of Pathology and Laboratory Medicine, |
RCV001355073 | SCV001549842 | uncertain significance | not provided | no assertion criteria provided | clinical testing | The ZNF423 p.Asn996Ser variant was not identified in the literature nor was it identified in ClinVar or Cosmic. The variant was identified in dbSNP (ID: rs368041529) and LOVD 3.0. The variant was also identified in control databases in 6 of 242352 chromosomes at a frequency of 0.000025 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 2 of 28530 chromosomes (freq: 0.00007), African in 1 of 16022 chromosomes (freq: 0.000062), Latino in 1 of 34046 chromosomes (freq: 0.000029) and European (non-Finnish) in 2 of 109282 chromosomes (freq: 0.000018); it was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), and Other populations. The p.Asn996 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. |