Submissions for variant NM_015102.5(NPHP4):c.2519G>A (p.Ser840Asn)

gnomAD frequency: 0.00147  dbSNP: rs147588666

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000334924	SCV000344322	likely benign	not specified	2016-11-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000861203	SCV001001455	likely benign	Nephronophthisis	2025-01-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001102311	SCV001258978	uncertain significance	Nephronophthisis 4	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001102312	SCV001258979	likely benign	Senior-Loken syndrome 4	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Genetic Services Laboratory, University of Chicago	RCV000334924	SCV002070082	uncertain significance	not specified	2021-09-20	criteria provided, single submitter	clinical testing	DNA sequence analysis of the NPHP4 gene demonstrated a sequence change, c.2519G>A, in exon 19 that results in an amino acid change, p.Ser840Asn. This sequence change has been described in the gnomAD database with a frequency of 0.47% in the African/African American subpopulation (dbSNP rs147588666). The p.Ser840Asn change affects a poorly conserved amino acid residue located in a domain of the NPHP4 protein that is not known to be functional. The p.Ser840Asn substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in individuals with NPHP4-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Ser840Asn change remains unknown at this time.
Ambry Genetics	RCV002518104	SCV003649898	uncertain significance	Inborn genetic diseases	2024-03-14	criteria provided, single submitter	clinical testing	The c.2519G>A (p.S840N) alteration is located in exon 19 (coding exon 18) of the NPHP4 gene. This alteration results from a G to A substitution at nucleotide position 2519, causing the serine (S) at amino acid position 840 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354108	SCV001548639	uncertain significance	not provided		no assertion criteria provided	clinical testing	The NPHP4 p.S840N variant was not identified in the literature but was identified in dbSNP (ID: rs147588666) and ClinVar (classified as likely benign by EGL Genetic Diagnostics, Illumina for Senior-Loken syndrome 4 and Invitae for nephronophthisis; and as uncertain significance by Illumina for nephronophthisis 4). The variant was identified in control databases in 133 of 279792 chromosomes at a frequency of 0.0004754, and was observed at the highest frequency in the African population in 113 of 24112 chromosomes (freq: 0.004686) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.S840 residue is not conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein; however this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a 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.