rs28939695

Positions:

chr19-35848142-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BA1

The NM_004646.4(NPHS1):c.1339G>A(p.Glu447Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00164 in 1,614,068 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 58 hom. )

Consequence

NPHS1
NM_004646.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:7

Conservation

PhyloP100: 3.96

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 Ig-like C2-type 5 (size 100) 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=0.009242237).

BP6

Variant 19-35848142-C-T is Benign according to our data. Variant chr19-35848142-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 180461.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=4, Uncertain_significance=2}. Variant chr19-35848142-C-T is described in Lovd as [Likely_benign].

BA1

GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0554 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHS1	NM_004646.4 linkuse as main transcript	c.1339G>A	p.Glu447Lys	missense_variant	11/29	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.1339G>A	p.Glu447Lys	missense_variant	11/29	1	NM_004646.4	ENSP00000368190	P2	O60500-1
NPHS1	ENST00000353632.6 linkuse as main transcript	c.1339G>A	p.Glu447Lys	missense_variant	11/28	5		ENSP00000343634	A2	O60500-2
NPHS1	ENST00000592132.1 linkuse as main transcript	n.346G>A		non_coding_transcript_exon_variant	4/4	3

Frequencies

GnomAD3 genomes

AF:

0.00120

AC:

182

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0316

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.00315

AC:

790

AN:

250542

Hom.:

AF XY:

0.00306

AC XY:

415

AN XY:

135694

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0412

Gnomad SAS exome

AF:

0.000588

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.00169

AC:

2465

AN:

1461760

Hom.:

Cov.:

AF XY:

0.00167

AC XY:

1216

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0574

Gnomad4 SAS exome

AF:

0.000614

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000288

Gnomad4 OTH exome

AF:

0.00161

GnomAD4 genome

AF:

0.00119

AC:

182

AN:

152308

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0316

Gnomad4 SAS

AF:

0.00186

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000235

Hom.:

Bravo

AF:

0.00122

ExAC

AF:

0.00287

AC:

348

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Finnish congenital nephrotic syndrome

Uncertain:1Benign: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.	May 04, 2020	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 15, 2021	This variant is associated with the following publications: (PMID: 20981092, 27019444, 29259860, 28476686, 29382012, 12631336, 24142548, 10652016, 11317351, 27882743, 26248470, 31216994, 31456999, 31180159, 31308032, 31788464) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Focal segmental glomerulosclerosis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 07, 2020

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 26, 2015

- -

Proteinuria

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Blueprint Genetics

Sep 17, 2014

- -

Congenital nephrotic syndrome

Benign:1

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 rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.43

T;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.89

D;D

MetaRNN

Benign

0.0092

T;T

MetaSVM

Benign

-0.33

MutationAssessor

Uncertain

2.4

M;M

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.7

N;N

REVEL

Uncertain

0.55

Sift

Benign

0.16

T;T

Sift4G

Uncertain

0.013

D;D

Polyphen

1.0

D;.

Vest4

0.48

MVP

0.94

MPC

0.74

ClinPred

0.059

GERP RS

5.0

Varity_R

0.44

gMVP

0.70

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