ClinVar Miner

Submissions for variant NM_015102.5(NPHP4):c.1440G>A (p.Ser480=)

gnomAD frequency: 0.00022  dbSNP: rs374690894
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000598206 SCV000702618 uncertain significance not provided 2018-02-08 criteria provided, single submitter clinical testing
Invitae RCV001257064 SCV001006560 likely benign Nephronophthisis 2024-01-18 criteria provided, single submitter clinical testing
Baylor Genetics RCV001334815 SCV001527779 uncertain significance Nephronophthisis 4 2018-04-10 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000598206 SCV001550097 uncertain significance not provided no assertion criteria provided clinical testing The NPHP4 p.(Arg25Gln) variant was not identified in the literature nor was it identified in Cosmic, LOVD 3.0, The variant was also identified in dbSNP (ID: rs374690894) and and ClinVar (classfied as "uncertain significance" by EGL Genetic diagnostic) databases. The variant was identified in control databases in 30 of 278808 chromosomes (278808 homozygous) at a frequency of 0.00011 (Genome Aggregation Database Feb 27, 2017). The variant was not observed in the African, East Asian, Other, European (non-Finnish), South Asian, Latino, Ashkenazi Jewish, and European (Finnish) populations. The p.Arg25 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The p.(Arg25Gln) variant occurs in the last three bases of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. In addition, 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. 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.

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