rs73928330

Variant summary

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

The NM_004646.4(NPHS1):c.43G>C(p.Gly15Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000816 in 1,553,412 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict 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. G15E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0043 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00044 ( 6 hom. )

Consequence

NPHS1
NM_004646.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.393

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:

KIRREL2 (HGNC:):

KIRREL2 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=0.0106295645).

BP6

Variant 19-35851795-C-G is Benign according to our data. Variant chr19-35851795-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 259502.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=2, Uncertain_significance=1}.

BS2

High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHS1	NM_004646.4 linkuse as main transcript	c.43G>C	p.Gly15Arg	missense_variant	1/29	ENST00000378910.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHS1	ENST00000378910.10 linkuse as main transcript	c.43G>C	p.Gly15Arg	missense_variant	1/29	1	NM_004646.4	P2	O60500-1
NPHS1	ENST00000353632.6 linkuse as main transcript	c.43G>C	p.Gly15Arg	missense_variant	1/28	5		A2	O60500-2
NPHS1	ENST00000591817.1 linkuse as main transcript	n.560-123G>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00432

AC:

658

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0144

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00340

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:

0.0000147

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.000941

AC:

147

AN:

156240

Hom.:

AF XY:

0.000704

AC XY:

AN XY:

82424

show subpopulations

Gnomad AFR exome

AF:

0.0147

Gnomad AMR exome

AF:

0.000483

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:

0.0000505

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000435

AC:

610

AN:

1401146

Hom.:

Cov.:

AF XY:

0.000359

AC XY:

248

AN XY:

691282

show subpopulations

Gnomad4 AFR exome

AF:

0.0154

Gnomad4 AMR exome

AF:

0.000866

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000250

Gnomad4 OTH exome

AF:

0.00105

GnomAD4 genome

AF:

0.00431

AC:

657

AN:

152266

Hom.:

Cov.:

AF XY:

0.00443

AC XY:

330

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.0144

Gnomad4 AMR

AF:

0.00334

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.000662

Hom.:

Bravo

AF:

0.00509

ESP6500AA

AF:

0.0109

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000834

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Finnish congenital nephrotic syndrome

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 21, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Sep 26, 2017	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 16, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Congenital nephrotic syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.50

Cadd

Benign

Dann

Uncertain

0.98

DEOGEN2

Uncertain

0.43

T;.

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.72

T;T

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.1

L;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-2.6

D;D

REVEL

Benign

0.13

Sift

Uncertain

0.0030

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.0

B;.

Vest4

0.34

MutPred

0.75

Gain of MoRF binding (P = 0.0519);Gain of MoRF binding (P = 0.0519);

MVP

0.72

MPC

0.20

ClinPred

0.014

GERP RS

1.4

Varity_R

0.23

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