Submissions for variant NM_001379286.1(ZNF423):c.1655G>T (p.Gly552Val)

gnomAD frequency: 0.00158  dbSNP: rs34425379

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000178951	SCV000231133	uncertain significance	not provided	2014-07-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001078488	SCV000652405	likely benign	Nephronophthisis 14	2025-01-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000178951	SCV005909541	likely benign	not provided	2025-03-01	criteria provided, single submitter	clinical testing	ZNF423: BP4, BS1
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000178951	SCV001553051	uncertain significance	not provided		no assertion criteria provided	clinical testing	The ZNF423 p.Gly427Val variant was not identified in the literature but was identified in dbSNP (ID: rs34425379), LOVD 3.0 and ClinVar (classified as uncertain significance by EGL Genetic Diagnostics and as likely benign by Invitae). The variant was identified in control databases in 136 of 282704 chromosomes at a frequency of 0.0004811 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 116 of 24916 chromosomes (freq: 0.004656), Other in 4 of 7216 chromosomes (freq: 0.000554), Latino in 14 of 35438 chromosomes (freq: 0.000395) and European (non-Finnish) in 2 of 129102 chromosomes (freq: 0.000015), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), or South Asian populations. The p.Gly427 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 however three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing and the creation of a new 5' splice site. However, this has not been confirmed by RNA analysis and is not predictive enough to assume 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.
PreventionGenetics, part of Exact Sciences	RCV003937620	SCV004766253	likely benign	ZNF423-related disorder	2024-05-29	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).