rs116700257

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_004646.4(NPHS1):c.3562G>A(p.Ala1188Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000297 in 1,613,560 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0016 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 1 hom. )

Consequence

NPHS1
NM_004646.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: -0.105

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009373307).

BP6

Variant 19-35830876-C-T is Benign according to our data. Variant chr19-35830876-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 554227.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=2}.

BS2

High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHS1	NM_004646.4 linkuse as main transcript	c.3562G>A	p.Ala1188Thr	missense_variant	28/29	ENST00000378910.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHS1	ENST00000378910.10 linkuse as main transcript	c.3562G>A	p.Ala1188Thr	missense_variant	28/29	1	NM_004646.4	P2	O60500-1
NPHS1	ENST00000353632.6 linkuse as main transcript	c.3442G>A	p.Ala1148Thr	missense_variant	27/28	5		A2	O60500-2

Frequencies

GnomAD3 genomes

AF:

0.00158

AC:

240

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00548

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

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:

0.00191

GnomAD3 exomes

AF:

0.000390

AC:

AN:

251474

Hom.:

AF XY:

0.000258

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00578

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000164

AC:

240

AN:

1461232

Hom.:

Cov.:

AF XY:

0.000128

AC XY:

AN XY:

726998

show subpopulations

Gnomad4 AFR exome

AF:

0.00622

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.000298

GnomAD4 genome

AF:

0.00158

AC:

240

AN:

152328

Hom.:

Cov.:

AF XY:

0.00154

AC XY:

115

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.00546

Gnomad4 AMR

AF:

0.000589

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:

0.00189

Alfa

AF:

0.000340

Hom.:

Bravo

AF:

0.00176

ESP6500AA

AF:

0.00545

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000511

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 10, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 08, 2020	This variant is associated with the following publications: (PMID: 28117080) -

Finnish congenital nephrotic syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Counsyl	Oct 06, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Vasylyeva lab, Texas Tech University Health Sciences Center	Oct 06, 2017	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jul 07, 2022

Variant summary: NPHS1 c.3562G>A (p.Ala1188Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00042 in 252492 control chromosomes (gnomAD and Bonomo_2014), predominantly at a frequency of 0.0058 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in NPHS1 causing Nephrotic Syndrome, Type 1 phenotype (0.0034), suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.3562G>A has been reported in the literature in at least one heterozygous individual affected with Nephrotic Syndrome, without strong evidence for causality (e.g. Bierzynska_2017) and therefore this report does not provide unequivocal conclusions about association of the variant with disease. 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. Three laboratories classified the variant as benign (n=1)/likely benign (n=2), and one classified it as VUS. Based on the evidence outlined above, the variant was classified as likely benign. -

NPHS1-related condition

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 27, 2020

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

0.066

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.51

Cadd

Benign

3.2

Dann

Benign

0.95

DEOGEN2

Benign

0.31

T;.

Eigen

Benign

-0.96

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.015

LIST_S2

Benign

0.63

T;T

M_CAP

Benign

0.027

MetaRNN

Benign

0.0094

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.3

L;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.95

N;N

REVEL

Benign

0.049

Sift

Benign

0.058

T;T

Sift4G

Benign

0.17

T;T

Polyphen

0.38

B;.

Vest4

0.24

MVP

0.63

MPC

0.10

ClinPred

0.0033

GERP RS

-0.71

Varity_R

0.051

gMVP

0.12

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