rs437168

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004646.4(NPHS1):c.2289C>T(p.Val763=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0635 in 1,613,890 control chromosomes in the GnomAD database, including 10,206 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 4540 hom., cov: 32)

Exomes 𝑓: 0.053 ( 5666 hom. )

Consequence

NPHS1
NM_004646.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -1.07

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 Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 19-35843517-G-A is Benign according to our data. Variant chr19-35843517-G-A is described in ClinVar as [Benign]. Clinvar id is 259489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-35843517-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.07 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.45 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHS1	NM_004646.4 linkuse as main transcript	c.2289C>T	p.Val763=	synonymous_variant	17/29	ENST00000378910.10	NP_004637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHS1	ENST00000378910.10 linkuse as main transcript	c.2289C>T	p.Val763=	synonymous_variant	17/29	1	NM_004646.4	ENSP00000368190	P2	O60500-1
NPHS1	ENST00000585400.1 linkuse as main transcript	n.980C>T		non_coding_transcript_exon_variant	3/3	1
NPHS1	ENST00000353632.6 linkuse as main transcript	c.2289C>T	p.Val763=	synonymous_variant	17/28	5		ENSP00000343634	A2	O60500-2

Frequencies

GnomAD3 genomes

AF:

0.161

AC:

24457

AN:

152026

Hom.:

4509

Cov.:

show subpopulations

Gnomad AFR

AF:

0.455

Gnomad AMI

AF:

0.0373

Gnomad AMR

AF:

0.0771

Gnomad ASJ

AF:

0.0651

Gnomad EAS

AF:

0.152

Gnomad SAS

AF:

0.0713

Gnomad FIN

AF:

0.0411

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0349

Gnomad OTH

AF:

0.122

GnomAD3 exomes

AF:

0.0788

AC:

19829

AN:

251486

Hom.:

2196

AF XY:

0.0717

AC XY:

9742

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.461

Gnomad AMR exome

AF:

0.0372

Gnomad ASJ exome

AF:

0.0728

Gnomad EAS exome

AF:

0.154

Gnomad SAS exome

AF:

0.0695

Gnomad FIN exome

AF:

0.0419

Gnomad NFE exome

AF:

0.0359

Gnomad OTH exome

AF:

0.0594

GnomAD4 exome

AF:

0.0533

AC:

77898

AN:

1461746

Hom.:

5666

Cov.:

AF XY:

0.0523

AC XY:

38011

AN XY:

727186

show subpopulations

Gnomad4 AFR exome

AF:

0.467

Gnomad4 AMR exome

AF:

0.0431

Gnomad4 ASJ exome

AF:

0.0715

Gnomad4 EAS exome

AF:

0.168

Gnomad4 SAS exome

AF:

0.0681

Gnomad4 FIN exome

AF:

0.0431

Gnomad4 NFE exome

AF:

0.0348

Gnomad4 OTH exome

AF:

0.0732

GnomAD4 genome

AF:

0.161

AC:

24533

AN:

152144

Hom.:

4540

Cov.:

AF XY:

0.158

AC XY:

11740

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.455

Gnomad4 AMR

AF:

0.0770

Gnomad4 ASJ

AF:

0.0651

Gnomad4 EAS

AF:

0.151

Gnomad4 SAS

AF:

0.0712

Gnomad4 FIN

AF:

0.0411

Gnomad4 NFE

AF:

0.0350

Gnomad4 OTH

AF:

0.120

Alfa

AF:

0.0503

Hom.:

600

Bravo

AF:

0.178

Asia WGS

AF:

0.121

AC:

422

AN:

3478

EpiCase

AF:

0.0349

EpiControl

AF:

0.0414

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Finnish congenital nephrotic syndrome

Benign:5

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 28, 2017	- -

not provided

Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 31, 2016	Variant summary: The NPHS1 c.2289C>T (p.Val763Val) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 10368/121400 control chromosomes (1310 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.4543533 (4728/10406). This frequency is about 135 times the estimated maximal expected allele frequency of a pathogenic NPHS1 variant (0.0033541), suggesting this is a benign common polymorphism found primarily in the populations of African origin. Therefore, this variant is classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Congenital nephrotic syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

4.2

DANN

Benign

0.63

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