rs386833936

Positions:

• chr19-35831678-AC-A
• 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.3250del​(p.Val1084SerfsTer59) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,606,760 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 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: NPHS1 NM_004646.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• 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-AC-A is Pathogenic according to our data. Variant chr19-35831678-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 56496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-35831678-AC-A is described in Lovd as [Pathogenic]. Variant chr19-35831678-AC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHS1	NM_004646.4	c.3250del	p.Val1084SerfsTer59	frameshift_variant	24/29	ENST00000378910.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHS1	ENST00000378910.10	c.3250del	p.Val1084SerfsTer59	frameshift_variant	24/29	1	NM_004646.4	P2
NPHS1	ENST00000353632.6	c.3167-179del		intron_variant		5		A2

Frequencies

GnomAD3 genomes AF: 0.0000332 AC: 5 AN: 150662 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000979

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: 0.00

Gnomad OTH AF: 0.000484

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1456098 Hom.: 0 Cov.: 34 AF XY: 0.0000124 AC XY: 9 AN XY: 724130

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000234

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 0.00000631

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000332 AC: 5 AN: 150662 Hom.: 0 Cov.: 31 AF XY: 0.0000272 AC XY: 2 AN XY: 73494

Gnomad4 AFR AF: 0.0000979

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: 0.00

Gnomad4 OTH AF: 0.000484

Bravo AF: 0.0000340

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Finnish congenital nephrotic syndrome Pathogenic:8

Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 08, 2020	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Sep 02, 2021	ACMG codes: PVS1; PS4M, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 18, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 08, 2023	Variant summary: NPHS1 c.3250delG (p.Val1084SerfsX59) 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 5.5e-05 in 236910 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in NPHS1 causing Nephrotic Syndrome, Type 1 (5.5e-05 vs 0.0034), allowing no conclusion about variant significance. c.3250delG has been reported in the literature as a biallelic compound heterozygous genotype in individuals affected with congenital nephrotic syndrome of the Finnish type (Nephrotic Syndrome, Type 1). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jul 26, 2017	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 29, 2022	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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16518627, 31589614, 10577936) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 15, 2023	This sequence change creates a premature translational stop signal (p.Val1084Serfs*59) 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 individual(s) with NPHS1-related nephrotic syndrome (PMID: 10577936, 16518627). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 56496). For these reasons, this variant has been classified 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: rs386833935; hg19: chr19-36322580;