rs386833865

Variant names:

• chr19-35848708-G-A
• rs386833865
• NM_004646.4:c.1099C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PP3_Moderate PP5_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 benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: NPHS1 NM_004646.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 3.36
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• congenital nephrotic syndrome, Finnish type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Myriad Women’s Health, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_004646.4
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 56421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHS1	NM_004646.4	c.1099C>T	p.Arg367Cys	missense_variant	Exon 9 of 29	ENST00000378910.10	NP_004637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHS1	ENST00000378910.10	c.1099C>T	p.Arg367Cys	missense_variant	Exon 9 of 29	1	NM_004646.4	ENSP00000368190.4
NPHS1	ENST00000353632.6	c.1099C>T	p.Arg367Cys	missense_variant	Exon 9 of 28	5		ENSP00000343634.5
NPHS1	ENST00000592132.1	n.106C>T		non_coding_transcript_exon_variant	Exon 2 of 4	3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152162 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000398 AC: 10 AN: 251356 AF XY: 0.0000515

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000294 AC: 43 AN: 1461878 Hom.: 0 Cov.: 32 AF XY: 0.0000316 AC XY: 23 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000261 AC: 29 AN: 1112010

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152162 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74330

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000452 Hom.: 0

Bravo AF: 0.0000264

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Finnish congenital nephrotic syndrome Pathogenic:9

Sep 30, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 09, 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.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. -

Mar 17, 2024

Baylor Genetics

Significance: 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

- -

Nov 16, 2023

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 20, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 11, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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-

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

NPHS1-related disorder Pathogenic:1

Jan 19, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Aug 30, 2023

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 cysteine, which is neutral and slightly polar, at codon 367 of the NPHS1 protein (p.Arg367Cys). This variant is present in population databases (rs386833865, gnomAD 0.01%). This missense change has been observed in individuals with nephrotic syndrome (PMID: 21415313, 24742477, 31655822). ClinVar contains an entry for this variant (Variation ID: 56421). 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. Experimental studies have shown that this missense change affects NPHS1 function (PMID: 11726550). For these reasons, this variant has been classified as Pathogenic. -

Focal segmental glomerulosclerosis Pathogenic:1

Oct 18, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	D;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.79	T;T
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	0.050	D
MutationAssessor	Uncertain	2.4	M;M
PhyloP100		3.4
PrimateAI	Uncertain	0.57	T
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	D
GERP RS		4.4
Varity_R		0.49
gMVP		0.87
Mutation Taster		=10/90	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs386833865; hg19: chr19-36339610;