Submissions for variant NM_015102.5(NPHP4):c.2519G>A (p.Ser840Asn) (rs147588666)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000334924	SCV000344322	likely benign	not specified	2016-11-22	criteria provided, single submitter	clinical testing
Invitae	RCV000861203	SCV001001455	likely benign	Nephronophthisis	2020-12-03	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,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 Clinical Services Laboratory,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.
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.