rs138173172

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_004646.4(NPHS1):c.2746G>T(p.Ala916Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00285 in 1,614,122 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A916T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0021 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0029 ( 21 hom. )

Consequence

NPHS1
NM_004646.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:4

Conservation

PhyloP100: 3.75

Publications

11 publications found

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 Gene-Disease associations (from GenCC):

congenital nephrotic syndrome, Finnish type
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Myriad Women’s Health, G2P, Labcorp Genetics (formerly Invitae), ClinGen
familial idiopathic steroid-resistant nephrotic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

NPHS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.023090273).

BP6

Variant 19-35841784-C-A is Benign according to our data. Variant chr19-35841784-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 259491.

BS2

High Homozygotes in GnomAd4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHS1	NM_004646.4 link	c.2746G>T	p.Ala916Ser	missense_variant	Exon 20 of 29	ENST00000378910.10	NP_004637.1	O60500-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHS1	ENST00000378910.10 link	c.2746G>T	p.Ala916Ser	missense_variant	Exon 20 of 29	1	NM_004646.4	ENSP00000368190.4		O60500-1
NPHS1	ENST00000353632.6 link	c.2746G>T	p.Ala916Ser	missense_variant	Exon 20 of 28	5		ENSP00000343634.5		O60500-2

Frequencies

GnomAD3 genomes

AF:

0.00215

AC:

327

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000628

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.000983

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00392

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00191

AC:

480

AN:

251432

AF XY:

0.00199

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000694

Gnomad ASJ exome

AF:

0.00248

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000970

Gnomad NFE exome

AF:

0.00341

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00292

AC:

4269

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00286

AC XY:

2080

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33480

American (AMR)

AF:

0.000648

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00191

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000104

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00182

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00356

AC:

3957

AN:

1112000

Other (OTH)

AF:

0.00192

AC:

116

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

240

480

721

961

1201

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

252

378

504

630

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00215

AC:

327

AN:

152246

Hom.:

Cov.:

AF XY:

0.00176

AC XY:

131

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.000626

AC:

AN:

41548

American (AMR)

AF:

0.000981

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00113

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00392

AC:

267

AN:

68032

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00388

Hom.:

Bravo

AF:

0.00190

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00360

AC:

ExAC

AF:

0.00197

AC:

239

EpiCase

AF:

0.00360

EpiControl

AF:

0.00290

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Finnish congenital nephrotic syndrome

Uncertain:1Benign:1

Feb 17, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jun 17, 2020

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NPHS1: BS2 -

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Feb 24, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: NPHS1 c.2746G>T (p.Ala916Ser) results in a conservative amino acid change located in the Immunoglobulin subtype 2 domain (IPR003598) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 251432 control chromosomes, predominantly at a frequency of 0.0034 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in NPHS1 causing Nephrotic Syndrome, Type 1 (0.0019 vs 0.0034), allowing no conclusion about variant significance. c.2746G>T has been reported in the literature in settings of multigene panel testing of individuals with a variety of renal manifestations such as FSGS, minimal change nephrotic syndrome (example, Busher_2016, Gast_2016, Lehadenkari_2004). These report(s) do not provide unequivocal conclusions about association of the variant with Nephrotic Syndrome, Type 1. At-least one co-occurrence with another pathogenic variant(s) as an alternative molecular basis of disease has been reported (Gilbert_2017, mitochondrial DNA, m.3243A>G), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Kidney disorder

Uncertain:1

Apr 01, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital nephrotic syndrome

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

NPHS1-related disorder

Benign:1

May 21, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

T;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.78

T;T

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.023

T;T

MetaSVM

Uncertain

-0.21

MutationAssessor

Benign

0.93

L;L

PhyloP100

3.8

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.1

N;N

REVEL

Uncertain

0.33

Sift

Benign

0.032

D;D

Sift4G

Uncertain

0.023

D;D

Polyphen

1.0

D;.

Vest4

0.66

MVP

0.88

MPC

0.50

ClinPred

0.015

GERP RS

4.8

Varity_R

0.30

gMVP

0.74

Mutation Taster

=78/22

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over