rs386833873

Variant names:

Variant summary

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

The NM_004646.4(NPHS1):c.121_122delCT(p.Leu41AspfsTer50) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00044 in 1,614,008 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00040 ( 0 hom. )

Consequence

NPHS1
NM_004646.4 frameshift

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 0.797

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:

KIRREL2 (HGNC:18816): (kirre like nephrin family adhesion molecule 2) This gene encodes a type I transmembrane protein and member of the immunoglobulin superfamily of cell adhesion molecules. The encoded protein localizes to adherens junctions in pancreatic beta cells and regulates insulin secretion. Autoantibodies against the encoded protein have been detected in serum from patients with type 1 diabetes. This gene may also play a role in glomerular development and decreased expression of this gene has been observed in human glomerular diseases. This gene and the related opposite-strand gene nephrin (GeneID: 527362) are regulated by a bidirectional promoter. [provided by RefSeq, Jul 2016]

KIRREL2 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 19-35851608-CAG-C is Pathogenic according to our data. Variant chr19-35851608-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 56431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-35851608-CAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHS1	NM_004646.4 link	c.121_122delCT	p.Leu41AspfsTer50	frameshift_variant	Exon 2 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.121_122delCT	p.Leu41AspfsTer50	frameshift_variant	Exon 2 of 29	1	NM_004646.4	ENSP00000368190.4	O60500-1
NPHS1	ENST00000353632.6 link	c.121_122delCT	p.Leu41AspfsTer50	frameshift_variant	Exon 2 of 28	5		ENSP00000343634.5	O60500-2
NPHS1	ENST00000591817.1 link	n.41_42delCT		downstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.000848

AC:

129

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0112

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00108

AC:

266

AN:

245950

Hom.:

AF XY:

0.00105

AC XY:

140

AN XY:

133906

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:

0.00

Gnomad FIN exome

AF:

0.0113

Gnomad NFE exome

AF:

0.000192

Gnomad OTH exome

AF:

0.000661

GnomAD4 exome

AF:

0.000397

AC:

581

AN:

1461682

Hom.:

AF XY:

0.000377

AC XY:

274

AN XY:

727160

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:

0.00

Gnomad4 FIN exome

AF:

0.00945

Gnomad4 NFE exome

AF:

0.0000522

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.000847

AC:

129

AN:

152326

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0112

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000270

Hom.:

Bravo

AF:

0.0000113

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

Oct 17, 2014

Blueprint Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

NM_004646.3:c.121_122delCT in the NPHS1 gene is also known as Fin-major in publications. It has an allele frequency of 0.011 in European (Finnish) subpopulation in the gnomAD database. The NPHS1 c.121_122delCT (p.Leu41Aspfs) variant locates at the 2nd exon out of 29 exons of the biological transcript of NPHS1. It results in a premature termination codon, predicting to cause a truncated or absent NPHS1 protein due to nonsense mediated decay. Lenkkeri et al reported one American congenital Nephrotic Syndrome patient was a heterozygote for the Fin-major mutation, carrying a single base insertion in exon 24 of the other allele (PMID: 9915943). This variant also has been observed in many individuals with nephrotic syndrome, and is a common founder mutation in the Finnish population (PMID: 9660941; 9915943). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PVS1; PS4; PM3; PP4. -

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 15, 2016

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.121_122delCT (p.Leu41Aspfs) variant results in a premature termination codon, predicted to cause a truncated or absent NPHS1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest is a Finnish founder mutation known as Fin-major. The variant of interest has been found in the large, broad control population, ExAC, with an allele frequency of 114/113010, predominantly in the Finnish cohort, 80/5484, which is expected since the variant is indicated to be a Finnish founder mutation. The variant of interest has been reported in multiple affected individuals as homozygous and compound heterozygous. In addition, multiple clinical diagnostic laboratories/databases cite the variant as "pathogenic." Therefore, the variant of interest has been classified as "pathogenic." -

Jun 18, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 02, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 20, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_004646.3(NPHS1):c.121_122delCT(L41Dfs*50, aka Fin major) is classified as pathogenic in the context of NPHS1-related nephrotic syndrome. Sources cited for classification include the following: PMID 9660941, 9915943 and 23949594. Classification of NM_004646.3(NPHS1):c.121_122delCT(L41Dfs*50, aka Fin major) 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. -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Pathogenic:2

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Leu41Aspfs*50) 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 (rs386833873, gnomAD 1.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with nephrotic syndrome, and is a common founder mutation in the Finnish population (PMID: 9660941, 9915943). It is commonly reported in individuals of Finnish ancestry (PMID: 9660941, 9915943). This variant is also known as "Fin major". ClinVar contains an entry for this variant (Variation ID: 56431). For these reasons, this variant has been classified as Pathogenic. -

NPHS1-related disorder

Pathogenic:1

Jun 13, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NPHS1 c.121_122delCT variant is predicted to result in a frameshift and premature protein termination (p.Leu41Aspfs*50). This small deletion has been reported to be causative for congenital nephrotic syndrome and was documented as one of two typical Finnish pathogenic NPHS1 variants (Kestilä et al. 1998. PubMed ID: 9660941; Lenkkeri et al. 1999. PubMed ID: 9915943). This variant is reported in 1.1% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-36342510-CAG-C). Frameshift variants in NPHS1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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