rs386833873

Positions:

• chr19-35851608-CAG-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004646.4(NPHS1):​c.121_122delCT​(p.Leu41fs) 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 0.797

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]

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]

NPHS1 (HGNC:):

ACMG classification

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/exons	MANE	Protein	UniProt
NPHS1	NM_004646.4	c.121_122delCT	p.Leu41fs	frameshift_variant	2/29	ENST00000378910.10	NP_004637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHS1	ENST00000378910.10	c.121_122delCT	p.Leu41fs	frameshift_variant	2/29	1	NM_004646.4	ENSP00000368190.4
NPHS1	ENST00000353632.6	c.121_122delCT	p.Leu41fs	frameshift_variant	2/28	5		ENSP00000343634.5
NPHS1	ENST00000591817.1	n.*41_*42delCT		downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.000848 AC: 129 AN: 152208 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.00105 AC XY: 140 AN XY: 133906

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.: 0 AF XY: 0.000377 AC XY: 274 AN XY: 727160

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.: 0 Cov.: 32 AF XY: 0.00125 AC XY: 93 AN XY: 74486

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.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Finnish congenital nephrotic syndrome Pathogenic:9

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 15, 2016	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." -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 1998	- -
Pathogenic, no assertion criteria provided	clinical testing	Blueprint Genetics	Oct 17, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 20, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 02, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 20, 2019	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. -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	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. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	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. -
Pathogenic, criteria provided, single submitter	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -

NPHS1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 13, 2023

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

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

Other links and lift over

dbSNP: rs386833873; hg19: chr19-36342510;