chr19-35831116-G-A

Position:

chr19-35831116-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_004646.4(NPHS1):c.3418C>T(p.Arg1140Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000096 in 1,613,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1140H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000096 ( 0 hom. )

Consequence

NPHS1
NM_004646.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:4

Conservation

PhyloP100: 1.89

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2733047).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHS1	NM_004646.4 linkuse as main transcript	c.3418C>T	p.Arg1140Cys	missense_variant	27/29	ENST00000378910.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHS1	ENST00000378910.10 linkuse as main transcript	c.3418C>T	p.Arg1140Cys	missense_variant	27/29	1	NM_004646.4	P2	O60500-1
NPHS1	ENST00000353632.6 linkuse as main transcript	c.3298C>T	p.Arg1100Cys	missense_variant	26/28	5		A2	O60500-2

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.000176

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000103

AC:

AN:

251274

Hom.:

AF XY:

0.0000957

AC XY:

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000958

AC:

140

AN:

1461734

Hom.:

Cov.:

AF XY:

0.0000853

AC XY:

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000115

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152094

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.000176

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000261

Hom.:

Bravo

AF:

0.000113

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Finnish congenital nephrotic syndrome

Pathogenic:1Uncertain:2

Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Oct 01, 2021	NM_004646.3(NPHS1):c.3418C>T(R1140C) is a missense variant classified as a variant of uncertain significance in the context of nephrotic syndrome, NPHS1-related. R1140C has been observed in cases with relevant disease (PMID: 26346198, 20172850, 9915943). Functional assessments of this variant are available in the literature (PMID: 24142548, 15496146, 11726550). R1140C has been observed in population frequency databases (gnomAD NFE 0.02%). In summary, there is insufficient evidence to classify NM_004646.3(NPHS1):c.3418C>T(R1140C) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 10, 2022	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jul 31, 2024

Variant summary: NPHS1 c.3418C>T (p.Arg1140Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 251274 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in NPHS1 causing Nephrotic Syndrome, Type 1 (0.0001 vs 0.0034), allowing no conclusion about variant significance. c.3418C>T has been reported in the literature in individuals with clinical features of NPHS1-related conditions, however no supportive evidence for causality was provided (e.g. Lenkkeri_1999, Schoeb_2010, Gast_2016). These reports do not provide unequivocal conclusions about association of the variant with Nephrotic Syndrome, Type 1. Publications also reports experimental evidence evaluating an impact on protein function and demonstrated proper cell surface localization for the variant protein (e.g. Liu_2001, Miyai_2014), these data suggest that the variant doesn't substantially affect NPHS1 function, but do not provide unequivocal conclusions about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 9915943, 26346198, 20172850, 11726550, 24142548). ClinVar contains an entry for this variant (Variation ID: 56500). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 03, 2022

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1140 of the NPHS1 protein (p.Arg1140Cys). This variant is present in population databases (rs143092783, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of NPHS1-related conditions (PMID: 9915943, 26346198). ClinVar contains an entry for this variant (Variation ID: 56500). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change does not substantially affect NPHS1 function (PMID: 11726550, 24142548). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.28

T;.

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.80

T;T

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.27

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.0

N;.

MutationTaster

Benign

0.96

N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.2

N;N

REVEL

Uncertain

0.49

Sift

Uncertain

0.021

D;D

Sift4G

Uncertain

0.014

D;D

Polyphen

0.73

P;.

Vest4

0.34

MVP

0.76

MPC

0.24

ClinPred

0.048

GERP RS

1.6

Varity_R

0.093

gMVP

0.42

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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