NM_004646.4:c.2398C>T

Variant names:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1BP4_StrongBP6_Very_StrongBS2

The NM_004646.4(NPHS1):c.2398C>T(p.Arg800Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000999 in 1,614,076 control chromosomes in the GnomAD database, including 11 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0015 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00094 ( 8 hom. )

Consequence

NPHS1
NM_004646.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1U:1B:4

Conservation

PhyloP100: 1.34

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 -14 ACMG points.

PM1

In a domain Ig-like C2-type 7 (size 92) in uniprot entity NPHN_HUMAN there are 12 pathogenic changes around while only 1 benign (92%) in NM_004646.4

BP4

Computational evidence support a benign effect (MetaRNN=0.025007755).

BP6

Variant 19-35842487-G-A is Benign according to our data. Variant chr19-35842487-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 222761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-35842487-G-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHS1	NM_004646.4 link	c.2398C>T	p.Arg800Cys	missense_variant	Exon 18 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.2398C>T	p.Arg800Cys	missense_variant	Exon 18 of 29	1	NM_004646.4	ENSP00000368190.4		O60500-1
NPHS1	ENST00000353632.6 link	c.2398C>T	p.Arg800Cys	missense_variant	Exon 18 of 28	5		ENSP00000343634.5		O60500-2

Frequencies

GnomAD3 genomes

AF:

0.00153

AC:

232

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00771

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.0150

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00229

AC:

576

AN:

251448

Hom.:

AF XY:

0.00223

AC XY:

303

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00794

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.0162

Gnomad NFE exome

AF:

0.000448

Gnomad OTH exome

AF:

0.00310

GnomAD4 exome

AF:

0.000945

AC:

1381

AN:

1461864

Hom.:

Cov.:

AF XY:

0.000899

AC XY:

654

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00630

Gnomad4 SAS exome

AF:

0.000162

Gnomad4 FIN exome

AF:

0.0156

Gnomad4 NFE exome

AF:

0.000160

Gnomad4 OTH exome

AF:

0.00159

GnomAD4 genome

AF:

0.00152

AC:

232

AN:

152212

Hom.:

Cov.:

AF XY:

0.00220

AC XY:

164

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00773

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.0150

Gnomad4 NFE

AF:

0.000353

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.000555

Hom.:

Bravo

AF:

0.000616

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00194

AC:

235

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Uncertain:1Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Finnish congenital nephrotic syndrome

Uncertain:1Benign:3

Baylor Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 18, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 08, 2018

Counsyl

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 03, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Familial idiopathic steroid-resistant nephrotic syndrome

Pathogenic:1

Aug 06, 2015

Blueprint Genetics

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: clinical testing

- -

not provided

Benign:1

Oct 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.74

DEOGEN2

Benign

0.32

T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.084

LIST_S2

Benign

0.74

T;T

MetaRNN

Benign

0.025

T;T

MetaSVM

Benign

-0.79

MutationAssessor

Benign

1.6

L;L

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.20

Sift

Benign

0.17

T;T

Sift4G

Uncertain

0.033

D;D

Polyphen

0.011

B;.

Vest4

0.19

MVP

0.53

MPC

0.15

ClinPred

0.92

GERP RS

-0.19

Varity_R

0.22

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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