chr19-35831056-G-A

Position:

• chr19-35831056-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004646.4(NPHS1):​c.3478C>T​(p.Arg1160Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000551 in 1,613,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000060 (0 hom.)
• Consequence: NPHS1 NM_004646.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:22
• Conservation: PhyloP100: 0.829

Genes affected

NPHS1 (HGNC:7908): (NPHS1 adhesion molecule, nephrin) This gene encodes a member of the immunoglobulin family of cell adhesion molecules that functions in the glomerular filtration barrier in the kidney. The gene is primarily expressed in renal tissues, and the protein is a type-1 transmembrane protein found at the slit diaphragm of glomerular podocytes. The slit diaphragm is thought to function as an ultrafilter to exclude albumin and other plasma macromolecules in the formation of urine. Mutations in this gene result in Finnish-type congenital nephrosis 1, characterized by severe proteinuria and loss of the slit diaphragm and foot processes.[provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-35831056-G-A is Pathogenic according to our data. Variant chr19-35831056-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 6873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-35831056-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHS1	NM_004646.4	c.3478C>T	p.Arg1160Ter	stop_gained	27/29	ENST00000378910.10	NP_004637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHS1	ENST00000378910.10	c.3478C>T	p.Arg1160Ter	stop_gained	27/29	1	NM_004646.4	ENSP00000368190	P2
NPHS1	ENST00000353632.6	c.3358C>T	p.Arg1120Ter	stop_gained	26/28	5		ENSP00000343634	A2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152130 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000994 AC: 25 AN: 251434 Hom.: 0 AF XY: 0.000125 AC XY: 17 AN XY: 135902

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000602 AC: 88 AN: 1461784 Hom.: 0 Cov.: 33 AF XY: 0.0000688 AC XY: 50 AN XY: 727202

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000441

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152130 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74322

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000780 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:22

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Finnish congenital nephrotic syndrome Pathogenic:14

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jan 02, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 17, 2017	Variant summary: The NPHS1 c.3478C>T (p.Arg1160X) variant results in a premature termination codon, predicted to cause a truncated or absent NPHS1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Nonsense mutations nearby to this variant have been classified as pathogenic by our laboratory previously (e.g., c.3325C>T [p.Arg1109X]). One in silico tool predicts a damaging outcome for this variant. This variant was found in the large control database ExAC and in control cohorts in the literature at a frequency of 0.000074 (9/121544 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic NPHS1 variant (0.0033541). Numerous publications have found the variant among patient cohorts as a homozygous genotype. In particular, the variant appears to be a founder mutation in Maltese individuals, where a study showed that of 50 non-Finnish patients analyzed, 12 were homozygous for the variant, 9 of which were from Malta (Koziell_HMG_2002). Additionally, a functional study showed that the variant prevents recruitment of nephrin (the protein product of NPHS1) into the lipid raft at the plasma membrane, which is important for many cellular processes, such as polarized sorting of membrane proteins and signal transduction (Huber_HMG_2003). In addition, one reputable database has classified this variant as pathogenic, though the last evaluation was in 2002. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 23, 2020	- -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jun 25, 2017	Previously reported pathogenic nonsense variant reported in 16 patients (PMID: 11854170) with additional cases reported in literature. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 10, 2021	The NPHS1 c.3478C>T (p.Arg1160Ter) variant is a stop-gained variant that is predicted to result in an absent or truncated protein product. Across a selection of the available literature, this variant has been identified in a homozygous state in 25 individuals with congenital nephrotic syndrome and in a presumed homozygous state in four additional cases (Koziell et al. 2002; Ovunc et al. 2012; Lenkkeri et al. 2013; Lovric et al. 2014; Cil et al. 2015; Amr et al. 2020; Wong et al. 2021). It has been proposed as a founder variant in Malta and has also been reported in a presumed compound heterozygous state with another stop-gained variant in one individual and in a confirmed compound heterozygous state with the p.Tyr977Cys variant in four affected siblings (Ovunc et al. 2012; Wang et al. 2017). Some individuals with this variant presented with slow disease progression. The p.Arg1160Ter variant is reported at a frequency of 0.000392 in the South Asian population of the Genome Aggregation Database (version 2.1.1). Functional studies conducted in HEK293 cells showed that the truncated protein resulting from this variant does not interact with podocin and failed to be recruited by podocin into lipid rafts at the plasma membrane (Huber et al. 2003). Based on the collective evidence, the p.Arg1160Ter variant is classified as pathogenic for congenital nephrotic syndrome. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.010%). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000006873 / PMID: 9915943). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	May 20, 2023	The observed stop gained c.3478C>T(p.Arg1160Ter) variant in NPHS1 gene has been reported in homozygous or compound heterozygous state in individual(s) affected with nephrotic syndrome (Koziell A, et. al., 2002; Cil O, et. al., 2015; Wang F, et. al.,2017). Functional studies conducted in HEK293 cells showed that the truncated protein resulting from this variant does not interact with podocin and failed to be recruited by podocin into lipid rafts at the plasma membrane (Huber TB, et. al., 2003). This variant is present with an allele frequency of 0.01% in gnomAD Exomes database. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). Computational evidence (MutationTaster - disease causing) predicts conflicting evidence on protein structure and function for this variant. The nucleotide change c.3478C>T in NPHS1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Precision Medicine Center, Zhengzhou University	Dec 01, 2023	PVS1,PM2_p,PM3,PP4 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 15, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 28, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1. -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 30, 2019	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 19, 2024	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 32779909, 34859019, 24742477, 24498843, 25525159, 28204945, 16518627, 31456999, 32363171, 34426522, 33565430, 31589614, 32860008, 32604935, 35064937, 36245711, 9915943, 29127259, 33980730, 37204080, 35755072) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	This sequence change creates a premature translational stop signal (p.Arg1160*) in the NPHS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NPHS1 are known to be pathogenic (PMID: 11317351, 11854170, 12039988). This variant is present in population databases (rs267606919, gnomAD 0.04%). This premature translational stop signal has been observed in individuals with NPHS1-related conditions (PMID: 9915943, 16518627, 24742477, 24902943, 25720465, 28204945). ClinVar contains an entry for this variant (Variation ID: 6873). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Nephrotic syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Sydney Genome Diagnostics, Children's Hospital Westmead	May 10, 2019	This individual is heterozygous for a pathogenic variant, c.3478C>T, in the NPHS1 gene. This variant creates a premature stop codon p.(Arg1160*) and may result in a null allele due to nonsense-mediated mRNA decay. This variant has been reported in the gnomAD browser (http://gnomad.broadinstitute.org) with a very low allele frequency of 0.01% (25 out of 246,216 alleles). The c.3478C>T p.(Arg1160*) variant has been reported in several patients from India and Malta origin with the mild congenital nephrotic syndrome of Finnish type (CNF, Koziell et al 2002 Hum Mol Genet 11: 379-388; Heeringa et al 2008 Nephrol Dial Translplant 23: 3527-3533; Machuca et al 2010 J Am Soc Nephrol 21: 1209-1217; Wang et al 2016; HK J Paediatr 21: 294-297). This variant is considered to be pathogenic according to the ACMG guidelines (Evidence used: PVS1, PM2, PM3). -
Likely pathogenic, no assertion criteria provided	literature only	Yale Center for Mendelian Genomics, Yale University	Nov 10, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.25
Eigen_PC	Benign	-0.083
FATHMM_MKL	Benign	0.049	N
MutationTaster	Benign	1.0	A;A
Vest4		0.68
GERP RS		3.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs267606919; hg19: chr19-36321958;