rs114849139

Positions:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_004646.4(NPHS1):c.2869G>C(p.Val957Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000648 in 1,614,168 control chromosomes in the GnomAD database, including 13 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00072 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00064 ( 9 hom. )

Consequence

NPHS1
NM_004646.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:6

Conservation

PhyloP100: 3.23

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 -11 ACMG points.

PM1

In a domain Fibronectin type-III (size 95) in uniprot entity NPHN_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_004646.4

BP4

Computational evidence support a benign effect (MetaRNN=0.018834054).

BP6

Variant 19-35839554-C-G is Benign according to our data. Variant chr19-35839554-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 225423.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=3, Uncertain_significance=3}. Variant chr19-35839554-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000641 (937/1461886) while in subpopulation EAS AF= 0.0184 (729/39700). AF 95% confidence interval is 0.0173. There are 9 homozygotes in gnomad4_exome. There are 474 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHS1	NM_004646.4 linkuse as main transcript	c.2869G>C	p.Val957Leu	missense_variant	21/29	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.2869G>C	p.Val957Leu	missense_variant	21/29	1	NM_004646.4	ENSP00000368190	P2	O60500-1
NPHS1	ENST00000353632.6 linkuse as main transcript	c.2869G>C	p.Val957Leu	missense_variant	21/28	5		ENSP00000343634	A2	O60500-2

Frequencies

GnomAD3 genomes

AF:

0.000723

AC:

110

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0137

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00106

AC:

267

AN:

251432

Hom.:

AF XY:

0.000949

AC XY:

129

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0116

Gnomad SAS exome

AF:

0.000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000615

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000641

AC:

937

AN:

1461886

Hom.:

Cov.:

AF XY:

0.000652

AC XY:

474

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0184

Gnomad4 SAS exome

AF:

0.00107

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000351

Gnomad4 OTH exome

AF:

0.00111

GnomAD4 genome

AF:

0.000716

AC:

109

AN:

152282

Hom.:

Cov.:

AF XY:

0.000846

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.000578

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0135

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000506

Hom.:

Bravo

AF:

0.000627

ExAC

AF:

0.00119

AC:

144

Asia WGS

AF:

0.00837

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Finnish congenital nephrotic syndrome

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Dec 15, 2017	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 05, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Pars Genome Lab	May 18, 2021	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	NPHS1: PM5, BP4, BS1 -

Congenital nephrotic syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

T;.

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.77

T;T

MetaRNN

Benign

0.019

T;T

MetaSVM

Benign

-0.57

MutationAssessor

Benign

1.3

L;L

MutationTaster

Benign

0.90

D;D

PrimateAI

Benign

0.46

PROVEAN

Benign

-2.3

N;N

REVEL

Benign

0.28

Sift

Uncertain

0.0060

D;D

Sift4G

Uncertain

0.029

D;T

Polyphen

1.0

D;.

Vest4

0.79

MutPred

0.86

Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);

MVP

0.80

MPC

0.33

ClinPred

0.043

GERP RS

4.3

Varity_R

0.30

gMVP

0.55

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