rs138656762

Positions:

chr19-35839418-C-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PP3PP5_Very_Strong

The NM_004646.4(NPHS1):c.2928G>T(p.Arg976Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000477 in 1,614,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

NPHS1
NM_004646.4 missense, splice_region

Scores

Splicing: ADA: 0.9940

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 0.0570

Variant links:

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]

NPHS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1

In a domain Fibronectin type-III (size 95) in uniprot entity NPHN_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_004646.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.805

PP5

Variant 19-35839418-C-A is Pathogenic according to our data. Variant chr19-35839418-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-35839418-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHS1	NM_004646.4 linkuse as main transcript	c.2928G>T	p.Arg976Ser	missense_variant, splice_region_variant	22/29	ENST00000378910.10	NP_004637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHS1	ENST00000378910.10 linkuse as main transcript	c.2928G>T	p.Arg976Ser	missense_variant, splice_region_variant	22/29	1	NM_004646.4	ENSP00000368190	P2	O60500-1
NPHS1	ENST00000353632.6 linkuse as main transcript	c.2928G>T	p.Arg976Ser	missense_variant, splice_region_variant	22/28	5		ENSP00000343634	A2	O60500-2

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000437

AC:

AN:

251458

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

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:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000479

AC:

AN:

1461836

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000549

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000729

Hom.:

Bravo

AF:

0.0000567

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Finnish congenital nephrotic syndrome

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 16, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 10, 2017	Variant summary: The NPHS1 c.2928G>T (p.Arg976Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a missense change in the fibronectin type III and immunoglobulin-like domains (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). The variant is the first nucleotide at the intron 21-exon 22 junction and 5/5 splice prediction tools predict a significant impact on normal splicing. These predictions are supported by a functional study, where exon 22 was found to be constitutively skipped in the presence of the variant via mini-gene assay. However, this in vitro result was not confirmed in vivo due to lack of patient samples (Philippe_JASN_2008). The same study showed that trafficking of nephrin (encoded by NPHS1) to the cell membrane was not altered by the variant. In the literature, numerous patients with end-stage renal failure (ESRF), minimal-change glomerulonephritis (MCNS), and focal segmental glomerulosclerosis (FSGS) have been found to carry the variant, mostly in compound heterozygosity. One patient homozygous for the variant has mild steroid resistant nephrotic syndrome (SRNS) with late onset at 37 years old (Lovric_CJASN_2014). This variant was found in the large control database ExAC and in control cohorts from the literature at a frequency of 0.0000657 (8/121742 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic NPHS1 variant (0.0033541). One clinical diagnostic laboratory and one reputable database have classified this variant as likely pathogenic or pathogenic. Taken together, this variant is classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Apr 16, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 08, 2018	The NPHS1 c.2928G>T (p.Arg976Ser) variant has been reported across three studies in a total of ten probands in a compound heterozygous state with a diagnosis of steroid resistant nephrogenic syndrome or congenital nephrotic syndrome (Philippe et al. 2008; Santin et al. 2009; Schoeb et al. 2010). Control data are unavailable for this variant, which is reported at a frequency of 0.0002in the European population of the 1000 Genomes Project. In vitro exon trapping experiments are suggestive of the p.Arg976Ser variant causing altered splicing that excludes exon 22 from the NPHS1 transcript (Philippe et al. 2008). Based on the evidence, the p.Arg976Ser variant is classified as pathogenic for congenital nephrotic syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jun 10, 2022	The c.2928G>T;p.(Arg976Ser) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar Id: 188761; PMID: 27019444; 18614772; 24742477; 24902943) - PS4. The variant is present at low allele frequencies population databases (rs138656762– gnomAD 0.0004600%; ABraOM no frequency - http://abraom.ib.usp.br/) -PM2_supporting. The p.(Arg976Ser) was detected in trans with a Pathogenic variant (PMID: 18614772; 24742477; 24902943) - PM3_strong. In summary, the currently available evidence indicates that the variant is Pathogenic -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 976 of the NPHS1 protein (p.Arg976Ser). This variant is present in population databases (rs138656762, gnomAD 0.01%). This missense change has been observed in individual(s) with nephrotic syndrome (PMID: 18614772, 20172850, 24742477, 29474669). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 188761). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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	GeneDx	Dec 06, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18614772, 30647093, 31980526, 31589614, 21415313, 19812541, 20172850, 20507940, 21782134, 20333530, 28844315, 29992269, 27019444, 24902943, 24742477, 29474669) -

Nephrotic syndrome

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Sydney Genome Diagnostics, Children's Hospital Westmead	Aug 28, 2018	This patient is heterozygous for a known pathogenic variant, c.2928G>T (p.Arg976Ser), in the NPHS1 gene. This variant (dbSNP: rs138656762) has been previously reported in patients with congenital nephrotic syndrome of Finnish type (NPHS1) in the literature (Philippe et al 2008 J Am Soc Nephrol 19:1871-1878; Santin et al 2009 Kidney Int 76:1268-1276; Schoeb et al 2010 Nephrol Dial Transplant 25:2970-2976). -
Pathogenic, criteria provided, single submitter	clinical testing	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	Apr 04, 2022	- -

NPHS1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 19, 2022

The NPHS1 c.2928G>T variant is predicted to result in the amino acid substitution p.Arg976Ser. This variant is located at the first base of an exon, and is predicted to diminish the strength of the canonical splice site (Alamut Visual Plus v1.6.1). This variant has been reported in the homozygous and compound heterozygous states in several individuals with congenital nephrotic syndrome (Philippe et al. 2008. PubMed ID: 18614772; Lovric et al. 2014. PubMed ID: 24742477; Schoeb et al. 2010. PubMed ID: 201728506). This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-36330320-C-A). This variant is interpreted as pathogenic. -

Focal segmental glomerulosclerosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Mar 07, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Uncertain

0.069

BayesDel_noAF

Uncertain

0.090

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.52

D;.

Eigen

Benign

0.052

Eigen_PC

Benign

-0.050

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.79

T;T

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.80

D;D

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.8

L;L

MutationTaster

Benign

0.95

D;D

PrimateAI

Benign

0.39

PROVEAN

Pathogenic

-5.2

D;D

REVEL

Uncertain

0.45

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0060

D;D

Polyphen

0.99

D;.

Vest4

0.77

MutPred

0.77

Loss of methylation at R976 (P = 0.0306);Loss of methylation at R976 (P = 0.0306);

MVP

0.88

MPC

0.52

ClinPred

0.90

GERP RS

0.26

Varity_R

0.92

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Benign

0.72

SpliceAI score (max)

0.11

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over