ClinVar Miner

Submissions for variant NM_015102.5(NPHP4):c.2930C>T (p.Thr977Met)

gnomAD frequency: 0.00006  dbSNP: rs569364202
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals RCV001002718 SCV001156394 pathogenic Senior-Loken syndrome 4 2019-02-01 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001442994 SCV001645953 likely benign Nephronophthisis 2025-02-01 criteria provided, single submitter clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV002279703 SCV002564436 uncertain significance Nephronophthisis 4 2022-08-06 criteria provided, single submitter clinical testing A heterozygous missense variation in exon 21 of NPHP4 gene that resulted in the amino acid substitution of methionine for Threonine at codon 977 was detected. This variant has a minor allele frequency of 0.1%, and 0.01% in the 1000 genomes and gnomAD databases respectively. The in-silico predictions of the variant are possibly damaging by PolyPhen-2 (HumDiv) and damaging by SIFT and MutationTaster2. The reference codon/ is conserved across species. In summary the variant meets our criteria to be classified as a variant of uncertain significance.
Neuberg Centre For Genomic Medicine, NCGM RCV002279703 SCV005329607 uncertain significance Nephronophthisis 4 2023-05-20 criteria provided, single submitter clinical testing The observed missense variant c.2930C>T (p.Thr977Met) in the NPHP4 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency 0.04% in the gnomAD Exomes. The amino acid Threonine at position 977 is changed to a Methionine changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The residue is conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Fulgent Genetics, Fulgent Genetics RCV005021311 SCV005653615 likely benign Nephronophthisis 4; Senior-Loken syndrome 4 2024-02-19 criteria provided, single submitter clinical testing

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