rs137853042

Positions:

chr19-35831358-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_004646.4(NPHS1):c.3325C>T(p.Arg1109Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000632 in 1,613,818 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000068 ( 0 hom. )

Consequence

NPHS1
NM_004646.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 0.189

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 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-35831358-G-A is Pathogenic according to our data. Variant chr19-35831358-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 6867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-35831358-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHS1	NM_004646.4 linkuse as main transcript	c.3325C>T	p.Arg1109Ter	stop_gained	26/29	ENST00000378910.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHS1	ENST00000378910.10 linkuse as main transcript	c.3325C>T	p.Arg1109Ter	stop_gained	26/29	1	NM_004646.4	P2	O60500-1
NPHS1	ENST00000353632.6 linkuse as main transcript	c.3205C>T	p.Arg1069Ter	stop_gained	25/28	5		A2	O60500-2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

151978

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:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000155

AC:

AN:

251456

Hom.:

AF XY:

0.000155

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000601

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.000651

GnomAD4 exome

AF:

0.0000677

AC:

AN:

1461840

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00116

Gnomad4 NFE exome

AF:

0.0000252

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.0000197

AC:

AN:

151978

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74220

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:

0.000189

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000325

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.000206

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Finnish congenital nephrotic syndrome

Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 31, 2016	Variant summary: The NPHS1 c.3325C>T (p.Arg1109X) variant, also known as Fin-minor, results in a premature termination codon, predicted to cause a truncated or absent NPHS1 protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. This variant was found in 25/121560 control chromosomes at a frequency of 0.0002057, which is lower than the estimated maximal expected allele frequency of a pathogenic NPHS1 variant (0.0033541). This variant is a known pathogenic variant with consistent genotype-phenotype data and the variant is mainly found in Finnish population (Kestila_1998, Lenkkeri_1999, Patrakka_2000, Koziell_2002, Machuca_2010, Sadowski_2015). In vitro functional assay shows that this variant abrogates the binding of the protein to podocin (Huber_2003). Taken together, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 23, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 15, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Vasylyeva lab, Texas Tech University Health Sciences Center	Nov 23, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 06, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 16, 2024	The p.Arg1109X variant in NPHS1 has been reported in the homozygous or compound heterozygous state in >10 individuals with nephrotic syndrome (Kestilä 1998 PMID: 9660941, Sinha 2020 PMID: 31655822, Zhu 2022 PMID: 35755072). It has also been identified in 0.10% (64/63990) of Finnish chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID 6867). This nonsense variant leads to a premature termination codon at position 1109, which is predicted to lead to a truncated or absent protein. Loss of function of the NPHS1 gene is an established disease mechanism in autosomal recessive nephrotic syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nephrotic syndrome. ACMG/AMP Criteria applied: PM3_Very strong, PVS1. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 11, 2019	NM_004646.3(NPHS1):c.3325C>T(R1109, aka Fin minor) is classified as pathogenic in the context of nephrotic syndrome, NPHS1-related. Sources cited for classification include the following: PMID 20507940, 11854170, 10972661, 20172850, 9915943 and 9660941. Classification of NM_004646.3(NPHS1):c.3325C>T(R1109, aka Fin minor) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -

not provided

Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	This sequence change creates a premature translational stop signal (p.Arg1109*) in the NPHS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NPHS1 are known to be pathogenic (PMID: 11317351, 11854170, 12039988). This variant is present in population databases (rs137853042, gnomAD 0.06%). This premature translational stop signal has been observed in individual(s) with congenital nephrotic syndrome (PMID: 31655822). ClinVar contains an entry for this variant (Variation ID: 6867). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.21

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.067

MutationTaster

Benign

1.0

A;A

Vest4

0.76

GERP RS

2.9

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