chr19-35831678-A-AC

Position:

• chr19-35831678-A-AC

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.3250_3251insG​(p.Val1084GlyfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,606,824 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: NPHS1 NM_004646.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19
• Conservation: PhyloP100: 0.0300

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]

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 19-35831678-A-AC is Pathogenic according to our data. Variant chr19-35831678-A-AC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56497.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHS1	NM_004646.4	c.3250_3251insG	p.Val1084GlyfsTer12	frameshift_variant	24/29	ENST00000378910.10	NP_004637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHS1	ENST00000378910.10	c.3250_3251insG	p.Val1084GlyfsTer12	frameshift_variant	24/29	1	NM_004646.4	ENSP00000368190	P2
NPHS1	ENST00000353632.6	c.3167-179_3167-178insG		intron_variant		5		ENSP00000343634	A2

Frequencies

GnomAD3 genomes AF: 0.0000398 AC: 6 AN: 150662 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000735

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: 0.0000443

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000760 AC: 18 AN: 236910 Hom.: 0 AF XY: 0.0000545 AC XY: 7 AN XY: 128528

Gnomad AFR exome AF: 0.000135

Gnomad AMR exome AF: 0.0000906

Gnomad ASJ exome AF: 0.000103

Gnomad EAS exome AF: 0.0000572

Gnomad SAS exome AF: 0.0000339

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000941

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000152 AC: 221 AN: 1456162 Hom.: 0 Cov.: 34 AF XY: 0.000170 AC XY: 123 AN XY: 724184

Gnomad4 AFR exome AF: 0.0000903

Gnomad4 AMR exome AF: 0.000137

Gnomad4 ASJ exome AF: 0.0000768

Gnomad4 EAS exome AF: 0.0000761

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.0000569

Gnomad4 NFE exome AF: 0.000179

Gnomad4 OTH exome AF: 0.0000665

GnomAD4 genome AF: 0.0000398 AC: 6 AN: 150662 Hom.: 0 Cov.: 31 AF XY: 0.0000408 AC XY: 3 AN XY: 73494

Gnomad4 AFR AF: 0.0000735

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: 0.0000443

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Finnish congenital nephrotic syndrome Pathogenic:13

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 13, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 08, 2018	Variant summary: NPHS1 c.3250dupG (p.Val1084GlyfsX12) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00023 in 82306 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in NPHS1 causing Nephrotic Syndrome, Type 1 (0.00023 vs 0.0034), allowing no conclusion about variant significance. c.3250dupG has been reported in the literature in multiple individuals affected with Nephrotic Syndrome, Type 1 (e.g. Heeringa 2008, Sadowski 2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Apr 20, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Jan 29, 2019	- -
Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Feb 09, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	Mar 26, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 29, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Dec 21, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with nephrotic syndrome type 1 (MIM# 256300). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2 and v3: 25 heterozygotes, 0 homozygotes. (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in multiple unrelated individuals. This variant has been reported in multiple individuals with nephrotic syndrome (PMID: 35102923, 19194555, 22653594, 28392951, 25407002, ClinVar, LOVD). (SP) 1201 - Heterozygous variant detected in trans with a second likely pathogenic heterozygous variant (p.(Gly796Glu)) in a recessive disease. (I) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The frameshift variant c.3250dup p.Val1084GlyfsTer12 in the NPHS1 gene has been reported previously in a heterozygous state in individuals affected with Congenital Nephrotic Syndrome and Steroid-Resistant Nephrotic Syndrome SRNS Bullich et al., 2015; Nguyen et al., 2017. This variant is reported with the allele frequency 0.007% in the gnomAD Exomes and novel not in any individuals in 1000 Genomes. It is submitted to ClinVar as Likely Pathogenic/ Pathogenic Multiple submissions. This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2024	Identified with a second NPHS1 variant, either phase unknown or confirmed on the opposite allele (in trans) in multiple unrelated patients with congenital nephrotic syndrome referred for genetic testing at GeneDx and in the literature (PMID: 9660941, 23949594, 19194555); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 23949594, 9660941, 19194555) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	This sequence change creates a premature translational stop signal (p.Val1084Glyfs*12) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with nephrotic syndrome (PMID: 9660941, 19194555, 23949594, 28392951). ClinVar contains an entry for this variant (Variation ID: 56497). 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. -

Nephrotic syndrome Pathogenic:2

Likely pathogenic, no assertion criteria provided	literature only	Yale Center for Mendelian Genomics, Yale University	Nov 10, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Sydney Genome Diagnostics, Children's Hospital Westmead	Aug 28, 2018	This patient is also heterozygous for a known pathogenic variant, c.3250dup, in the NPHS1 gene. This frameshifting variant (dbSNP: rs386833936) is predicted to create a premature stop codon 11 positions downstream (p.Val1084Glyfs*12), and may result in a null allele due to nonsense-mediated mRNA decay. This variant is considered to be pathogenic, and has been previously reported in patients with congenital nephrotic syndrome of Finnish type in the literature (Kestila et al 1998 Mol Cell 1:575-582; Lenkkeri et al 1999 Am J Hum Genet 64:51-61; Lee et al 2009 J Korean Med Sci 24:S210-S214). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs386833935; hg19: chr19-36322580;