rs386833865

Positions:

chr19-35848708-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_004646.4(NPHS1):c.1099C>T(p.Arg367Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,614,040 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R367H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

NPHS1
NM_004646.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.36

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 16 ACMG points.

PM1

In a domain Ig-like C2-type 4 (size 94) in uniprot entity NPHN_HUMAN there are 15 pathogenic changes around while only 1 benign (94%) in NM_004646.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-35848707-C-T is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.905

PP5

Variant 19-35848708-G-A is Pathogenic according to our data. Variant chr19-35848708-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-35848708-G-A is described in Lovd as [Likely_pathogenic]. Variant chr19-35848708-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHS1	NM_004646.4 linkuse as main transcript	c.1099C>T	p.Arg367Cys	missense_variant	9/29	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.1099C>T	p.Arg367Cys	missense_variant	9/29	1	NM_004646.4	ENSP00000368190	P2	O60500-1
NPHS1	ENST00000353632.6 linkuse as main transcript	c.1099C>T	p.Arg367Cys	missense_variant	9/28	5		ENSP00000343634	A2	O60500-2
NPHS1	ENST00000592132.1 linkuse as main transcript	n.106C>T		non_coding_transcript_exon_variant	2/4	3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251356

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000294

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000151

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000261

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000478

Hom.:

Bravo

AF:

0.0000264

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

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:9

Likely pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Nov 16, 2023	A homozygous missense variant in exon 9 of the NPHS1 gene that results in the amino acid substitution of Cysteine for Arginine at codon 367 (p.Arg367Cys) was detected. The observed variant has previously been reported in patients affected with nephrotic syndrome [PMID:30013592]. The p.Arg367Cys variant has not been reported in the 1000 genomes databases and has a minor allele frequency of 0.002%, 0.004% and 0.003% in the gnomAD (v3.1), gnomdAD (v2.1) and topmed databases respectively. The in silico prediction of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across mammals. In summary, the variant meets our criteria to be classified as likely pathogenic. -
Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 17, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 30, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 27, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	May 20, 2023	The observed missense c.1099C>T(p.Arg367Cys) variant in NPHS1 gene has been reported in homozygous or compound heterozygous state in individual(s) affected with nephrotic Syndrome (Sinha R, et. al., 2020; Lovric S, et. al., 2014). Experimental studies have shown that this missense change affects NPHS1 function (Liu L, et. al., 2001). This variant is present with an allele frequency of 0.004% in gnomAD Exomes database. This variant has been reported to the ClinVar database as Likely pathogenic/ Pathogenic(multiple submissions). Multiple lines of computational evidence (Polyphen - probably damaging , SIFT - damaging and MutationTaster - disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Arg367Cys in NPHS1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 367 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 09, 2017	Variant summary: The NPHS1 c.1099C>T (p.Arg367Cys) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 10/246176 control chromosomes at a frequency of 0.0000406, which does not exceed the estimated maximal expected allele frequency of a pathogenic NPHS1 variant (0.0033541). The variant has been reported in affected individuals in the literature, and has been described as an Indian founder mutation (Sadowski_2015). In in vitro studies, the variant was shown to result in the absence of cell-surface localization (Liu_2001). In addition, one clinical diagnostic laboratory classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic. -

NPHS1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 19, 2024

The NPHS1 c.1099C>T variant is predicted to result in the amino acid substitution p.Arg367Cys. This variant has been repeatedly reported in the compound heterozygous or homozygous state in individuals with congenital nephrotic syndrome (Lenkkeri et al. 1999. PubMed ID: 9915943; Liu L et al. 2001. PubMed ID: 11726550; Lovric S et al. 2014. PubMed ID: 24742477; Sinha R et al. 2019. PubMed ID: 31655822; Koziell A et al. 2002. PubMed ID: 11854170; Joshi A et al. 2021. PubMed ID: 33980730). This variant is reported as a possible founder variant from India (Sadowski et al. 2015. PubMed ID: 25349199). This variant is reported in 0.013% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 30, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects NPHS1 function (PMID: 11726550). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NPHS1 protein function. ClinVar contains an entry for this variant (Variation ID: 56421). This missense change has been observed in individuals with nephrotic syndrome (PMID: 21415313, 24742477, 31655822). This variant is present in population databases (rs386833865, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 367 of the NPHS1 protein (p.Arg367Cys). -

Focal segmental glomerulosclerosis

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.040

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.79

D;.

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.79

T;T

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.90

D;D

MetaSVM

Uncertain

0.050

MutationAssessor

Uncertain

2.4

M;M

MutationTaster

Benign

0.99

D;D

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-4.5

D;D

REVEL

Pathogenic

0.66

Sift

Uncertain

0.014

D;D

Sift4G

Uncertain

0.0070

D;D

Polyphen

1.0

D;.

Vest4

0.78

MVP

0.88

MPC

0.80

ClinPred

0.92

GERP RS

4.4

Varity_R

0.49

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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