rs74315343

chr1-179561328-G-A

Variant summary

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

The NM_014625.4(NPHS2):c.412C>T(p.Arg138Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,612,836 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R138R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: NPHS2 NM_014625.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 3.54

Genes affected

NPHS2 (HGNC:13394): (NPHS2 stomatin family member, podocin) This gene encodes a protein that plays a role in the regulation of glomerular permeability. Mutations in this gene cause steroid-resistant nephrotic syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

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 1-179561328-G-A is Pathogenic according to our data. Variant chr1-179561328-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 5361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-179561328-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHS2	NM_014625.4	c.412C>T	p.Arg138Ter	stop_gained	3/8	ENST00000367615.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHS2	ENST00000367615.9	c.412C>T	p.Arg138Ter	stop_gained	3/8	1	NM_014625.4	P1
NPHS2	ENST00000367616.4	c.412C>T	p.Arg138Ter	stop_gained	3/7	1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151938 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251298 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135822

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1460898 Hom.: 0 Cov.: 29 AF XY: 0.0000110 AC XY: 8 AN XY: 726824

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151938 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74188

Gnomad4 AFR AF: 0.0000242

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: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000896 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nephrotic syndrome, type 2 Pathogenic:7

Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Dec 03, 2018	The heterozygous p.Arg138Ter variant in NPHS2 was identified by our study in the compound heterozygous state, with a pathogenic variant, in one individual with nephrotic syndrome. This variant has also been reported pathogenic in ClinVar (Variation ID: 5361). The p.Arg138Ter variant in NPHS2 has been reported in 15 Arab-Israeli individuals with nephrotic syndrome, segregated with disease in 9 affected relatives from 2 families (PMID: 11805168), and has been identified in 0.006538% (1/15296) of African chromosomes, 0.002979% (1/33564) of Latino chromosomes, and 0.001792% (2/111604) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs74315343). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 138, which is predicted to lead to a truncated or absent protein. Loss of function of the NPHS2 gene is an established disease mechanism in autosomal recessive nephrotic syndrome. The presence of this variant in combination with a pathogenic variant reported in this study and in an individual with nephrotic syndrome increases the likelihood that the p.Arg138Ter variant is pathogenic. In summary, this variant meets criteria to be classified as pathogenic for nephrotic syndrome in an autosomal recessive manner based on the predicted impact of the variant and cosegration with disease in multiple families. ACMG/AMP Criteria applied: PM2, PVS1, PP1_Moderate, PM3 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The stop gained p.R138* in NPHS2 (NM_014625.4) has been reported previously in individual(s) with nephrotic syndrome (Boute et al, 2000). The p.R138* variant has a GnomAD frequency of 0.001592 % and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. The p.R138* variant is a loss of function variant in the gene NPHS2, which is intolerant of Loss of Function variants. The nucleotide change in NPHS2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates.For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 04, 2019	NM_014625.2(NPHS2):c.412C>T(R138*) is classified as pathogenic in the context of NPHS2-related nephrotic syndrome. Sources cited for classification include the following: PMID 17899208, 11805168, 20798252, 10742096 and 14570703. Classification of NM_014625.2(NPHS2):c.412C>T(R138*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 26, 2023	- -
Pathogenic, criteria provided, single submitter	research	Molecular Biology Laboratory, Fundació Puigvert	Feb 01, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2007	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 26, 2023	This sequence change creates a premature translational stop signal (p.Arg138*) in the NPHS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NPHS2 are known to be pathogenic (PMID: 10742096, 14701729, 15253708, 23595123). This variant is present in population databases (rs74315343, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with nephrotic syndrome (PMID: 10742096). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5361). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects NPHS2 function (PMID: 14570703). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 31, 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 symptomatic patient, and found in general population data that is consistent with pathogenicity. Occurs in three or more cases with a recessive pathogenic variant in the same gene. Damaging to protein function(s) relevant to disease mechanism. Strong co-segregation with disease in affected and unaffected individuals, but from a single family. -

Steroid-resistant nephrotic syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Focal segmental glomerulosclerosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 06, 2022

- -

Idiopathic nephrotic syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 01, 2022

Variant summary: NPHS2 c.412C>T (p.Arg138X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.6e-05 in 251298 control chromosomes (gnomAD). c.412C>T has been reported in the literature in multiple individuals affected with Nephrotic Syndrome, Type 2 (e.g. Boute_2000, Frishberg_2006). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant results in the loss of both homo-oligomerization and interaction with nephrin (Huber_2003). Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.62
Cadd	Pathogenic	45
Dann	Uncertain	1.0
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.93	D
MutationTaster	Benign	1.0	A;A
Vest4		0.96
GERP RS		4.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.49		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.49		Position offset: 33

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

Publications

LitVar

Other links and lift over

dbSNP: rs74315343; hg19: chr1-179530463; COSMIC: COSV62634573;