rs113825926

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_004646.4(NPHS1):c.881C>T(p.Thr294Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.011 in 1,609,588 control chromosomes in the GnomAD database, including 138 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T294T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0083 ( 8 hom., cov: 32)

Exomes 𝑓: 0.011 ( 130 hom. )

Consequence

NPHS1
NM_004646.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.0780

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0051461756).

BP6

Variant 19-35849107-G-A is Benign according to our data. Variant chr19-35849107-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 259508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-35849107-G-A is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHS1	NM_004646.4 linkuse as main transcript	c.881C>T	p.Thr294Ile	missense_variant	8/29	ENST00000378910.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHS1	ENST00000378910.10 linkuse as main transcript	c.881C>T	p.Thr294Ile	missense_variant	8/29	1	NM_004646.4	P2	O60500-1
NPHS1	ENST00000353632.6 linkuse as main transcript	c.881C>T	p.Thr294Ile	missense_variant	8/28	5		A2	O60500-2

Frequencies

GnomAD3 genomes

AF:

0.00835

AC:

1271

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00367

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.00510

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.00630

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0137

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00774

AC:

1897

AN:

245030

Hom.:

AF XY:

0.00803

AC XY:

1070

AN XY:

133220

show subpopulations

Gnomad AFR exome

AF:

0.00446

Gnomad AMR exome

AF:

0.00307

Gnomad ASJ exome

AF:

0.00110

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00405

Gnomad FIN exome

AF:

0.00497

Gnomad NFE exome

AF:

0.0130

Gnomad OTH exome

AF:

0.00856

GnomAD4 exome

AF:

0.0112

AC:

16375

AN:

1457236

Hom.:

130

Cov.:

AF XY:

0.0112

AC XY:

8120

AN XY:

725134

show subpopulations

Gnomad4 AFR exome

AF:

0.00376

Gnomad4 AMR exome

AF:

0.00331

Gnomad4 ASJ exome

AF:

0.00111

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00393

Gnomad4 FIN exome

AF:

0.00697

Gnomad4 NFE exome

AF:

0.0134

Gnomad4 OTH exome

AF:

0.00766

GnomAD4 genome

AF:

0.00835

AC:

1272

AN:

152352

Hom.:

Cov.:

AF XY:

0.00809

AC XY:

603

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.00368

Gnomad4 AMR

AF:

0.00510

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00331

Gnomad4 FIN

AF:

0.00630

Gnomad4 NFE

AF:

0.0137

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.0119

Hom.:

Bravo

AF:

0.00794

TwinsUK

AF:

0.0111

AC:

ALSPAC

AF:

0.0130

AC:

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.0119

AC:

102

ExAC

AF:

0.00871

AC:

1057

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0115

EpiControl

AF:

0.0117

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 03, 2016	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 07, 2021	This variant is associated with the following publications: (PMID: 15086927, 20507940, 11317351, 20981092, 26346198, 31216994) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	NPHS1: BP4, BS1, BS2 -

Focal segmental glomerulosclerosis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 19, 2022

- -

Finnish congenital nephrotic syndrome

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Congenital nephrotic syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.52

Cadd

Benign

9.8

Dann

Uncertain

0.99

DEOGEN2

Uncertain

0.50

D;.

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.71

T;T

MetaRNN

Benign

0.0051

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.69

N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.071

Sift

Benign

0.060

T;D

Sift4G

Benign

0.28

T;T

Polyphen

0.097

B;.

Vest4

0.17

MVP

0.69

MPC

0.20

ClinPred

0.0023

GERP RS

-1.0

Varity_R

0.084

gMVP

0.43

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