NM_004646.4:c.1379G>A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong

The NM_004646.4(NPHS1):c.1379G>A(p.Arg460Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,613,948 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

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

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

NPHS1
NM_004646.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 1.46

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 12 ACMG points.

PM1

In a domain Ig-like C2-type 5 (size 100) 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;

PP5

Variant 19-35848102-C-T is Pathogenic according to our data. Variant chr19-35848102-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-35848102-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHS1	NM_004646.4 link	c.1379G>A	p.Arg460Gln	missense_variant	Exon 11 of 29	ENST00000378910.10	NP_004637.1	O60500-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NPHS1	ENST00000378910.10 link	c.1379G>A	p.Arg460Gln	missense_variant	Exon 11 of 29	1	NM_004646.4	ENSP00000368190.4	O60500-1
NPHS1	ENST00000353632.6 link	c.1379G>A	p.Arg460Gln	missense_variant	Exon 11 of 28	5		ENSP00000343634.5	O60500-2
NPHS1	ENST00000592132.1 link	n.386G>A		non_coding_transcript_exon_variant	Exon 4 of 4	3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152202

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250476

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135620

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461746

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727168

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74366

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Finnish congenital nephrotic syndrome

Pathogenic:11

Jan 19, 2021

Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 03, 2022

Vasylyeva lab, Texas Tech University Health Sciences Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 07, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 03, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000056438, PMID:11317351, PS1_S). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals(PMID: 30655312, 21125408, 19194555, PM3_S). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Sep 14, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The NPHS1 c.1379G>A (p.Arg460Gln) variant located in the Immunoglobulin-like fold domain (via InterPro) involves the alteration of a non-conserved nucleotide and 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 2/215308 control chromosomes at a frequency of 0.0000093, which does not exceed the estimated maximal expected allele frequency of a pathogenic NPHS1 variant (0.0033541). Multiple publications have cited the variant in homozygous and compound heterozygous affected pts. A functional study, Philippe_2008 indicates that the variant was shown to traffic normally in the cell and to homodimerize and to heterodimerize with NEPH1, but they suggest that additional studies are needed to evaluate whether missense variants that traffic to the membrane affect nephrin phosphorylation, actin reorganization in the cytoskeleton of podocytes, or downstream signaling events involved in transcriptional regulation and apoptosis. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic. -

Apr 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2023

Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jul 20, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Across a selection of the available literature, the NPHS1 c.1379G>A (p.Arg460Gln) variant has been identified in at least 11 individuals with congenital Finnish nephrosis. Specifically, the p.Arg460Gln variant was reported in a homozygous state in six individuals, in a compound heterozygous state in three individuals, and in a heterozygous state in two individuals (Sako et al. 2005; Heeringa et al. 2008; Lee et al. 2009; Machuca et al. 2010; Schoeb et al. 2010). The p.Arg460Gln variant was also found in a heterozygous state in the unaffected mother of an affected heterozygote (Sako et al. 2005). Two of the compound heterozygotes have null variants on the second allele (Heeringa et al. 2008; Machuca et al. 2010). Control data are unavailable for this variant, which is reported at a frequency of 0.000183 in the Other population of the Genome Aggregation Database but this is based on one allele so the variant is presumed to be rare. Based on the evidence, the p.Arg460Gln 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. -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 29, 2014

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

not provided

Pathogenic:2

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NPHS1: PM3:Very Strong, PM2, PS4:Moderate, PS3:Supporting, BP4 -

Jan 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 460 of the NPHS1 protein (p.Arg460Gln). This variant is present in population databases (rs386833880, gnomAD 0.003%). This missense change has been observed in individual(s) with nephrotic syndrome (PMID: 19194555, 21125408, 21415313, 30655312). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 56438). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Kidney disorder

Pathogenic:1

Dec 12, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nephrotic syndrome

Pathogenic:1

Nov 10, 2017

Yale Center for Mendelian Genomics, Yale University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Uncertain

0.025

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.34

T;.

Eigen

Uncertain

0.19

Eigen_PC

Benign

0.22

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.71

T;T

M_CAP

Benign

0.030

MetaRNN

Uncertain

0.43

T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.6

L;L

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.72

N;N

REVEL

Uncertain

0.44

Sift

Benign

0.19

T;T

Sift4G

Benign

0.20

T;T

Polyphen

0.97

D;.

Vest4

0.16

MutPred

0.87

Loss of MoRF binding (P = 0.0272);Loss of MoRF binding (P = 0.0272);

MVP

0.83

MPC

0.35

ClinPred

0.50

GERP RS

4.0

Varity_R

0.14

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.45

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.45

Position offset: -1

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