rs4806213

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004646.4(NPHS1):c.3230A>G(p.Asn1077Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 1,602,890 control chromosomes in the GnomAD database, including 8,826 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 881 hom., cov: 31)

Exomes 𝑓: 0.10 ( 7945 hom. )

Consequence

NPHS1
NM_004646.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.914

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020531416).

BP6

Variant 19-35831699-T-C is Benign according to our data. Variant chr19-35831699-T-C is described in ClinVar as [Benign]. Clinvar id is 259496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-35831699-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHS1	NM_004646.4 linkuse as main transcript	c.3230A>G	p.Asn1077Ser	missense_variant	24/29	ENST00000378910.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHS1	ENST00000378910.10 linkuse as main transcript	c.3230A>G	p.Asn1077Ser	missense_variant	24/29	1	NM_004646.4	P2	O60500-1
NPHS1	ENST00000353632.6 linkuse as main transcript	c.3167-199A>G		intron_variant		5		A2	O60500-2

Frequencies

GnomAD3 genomes

AF:

0.105

AC:

15946

AN:

151246

Hom.:

880

Cov.:

show subpopulations

Gnomad AFR

AF:

0.126

Gnomad AMI

AF:

0.133

Gnomad AMR

AF:

0.0951

Gnomad ASJ

AF:

0.155

Gnomad EAS

AF:

0.0103

Gnomad SAS

AF:

0.107

Gnomad FIN

AF:

0.117

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.0980

Gnomad OTH

AF:

0.0935

GnomAD3 exomes

AF:

0.0970

AC:

22452

AN:

231452

Hom.:

1141

AF XY:

0.0977

AC XY:

12240

AN XY:

125268

show subpopulations

Gnomad AFR exome

AF:

0.123

Gnomad AMR exome

AF:

0.0865

Gnomad ASJ exome

AF:

0.153

Gnomad EAS exome

AF:

0.0102

Gnomad SAS exome

AF:

0.114

Gnomad FIN exome

AF:

0.110

Gnomad NFE exome

AF:

0.0980

Gnomad OTH exome

AF:

0.104

GnomAD4 exome

AF:

0.101

AC:

146169

AN:

1451526

Hom.:

7945

Cov.:

AF XY:

0.101

AC XY:

72803

AN XY:

721406

show subpopulations

Gnomad4 AFR exome

AF:

0.136

Gnomad4 AMR exome

AF:

0.0854

Gnomad4 ASJ exome

AF:

0.155

Gnomad4 EAS exome

AF:

0.00781

Gnomad4 SAS exome

AF:

0.113

Gnomad4 FIN exome

AF:

0.108

Gnomad4 NFE exome

AF:

0.101

Gnomad4 OTH exome

AF:

0.0999

GnomAD4 genome

AF:

0.106

AC:

15982

AN:

151364

Hom.:

881

Cov.:

AF XY:

0.106

AC XY:

7870

AN XY:

73920

show subpopulations

Gnomad4 AFR

AF:

0.126

Gnomad4 AMR

AF:

0.0953

Gnomad4 ASJ

AF:

0.155

Gnomad4 EAS

AF:

0.0103

Gnomad4 SAS

AF:

0.108

Gnomad4 FIN

AF:

0.117

Gnomad4 NFE

AF:

0.0980

Gnomad4 OTH

AF:

0.0930

Alfa

AF:

0.102

Hom.:

454

Bravo

AF:

0.103

TwinsUK

AF:

0.0998

AC:

370

ALSPAC

AF:

0.101

AC:

389

ESP6500AA

AF:

0.124

AC:

547

ESP6500EA

AF:

0.0966

AC:

831

ExAC

AF:

0.0929

AC:

11256

Asia WGS

AF:

0.0700

AC:

243

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Finnish congenital nephrotic syndrome

Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 20, 2015	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 2019	This variant is associated with the following publications: (PMID: 31216994, 28476686, 9915943, 15086927, 27884173, 12495287, 21228398, 20981092, 20507940) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 16, 2017	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 24, 2016	- -

Focal segmental glomerulosclerosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 27, 2022

- -

Congenital nephrotic syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.41

Cadd

Benign

Dann

Benign

0.96

DEOGEN2

Uncertain

0.58

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.79

MetaRNN

Benign

0.0021

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

MutationTaster

Benign

0.33

P;P

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-2.3

REVEL

Benign

0.11

Sift

Uncertain

0.018

Sift4G

Uncertain

0.026

Polyphen

0.010

Vest4

0.12

MPC

0.087

ClinPred

0.0042

GERP RS

1.7

Varity_R

0.068

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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