NM_004646.4:c.1619C>A

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP3BP6

The NM_004646.4(NPHS1):c.1619C>A(p.Ala540Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000953 in 1,422,266 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 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 0.00049 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 1 hom. )

Consequence

NPHS1
NM_004646.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: -0.101

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 Uncertain_significance. Variant got 4 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

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 19-35846016-G-T is Benign according to our data. Variant chr19-35846016-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 447874.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHS1	NM_004646.4 link	c.1619C>A	p.Ala540Glu	missense_variant	Exon 12 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.1619C>A	p.Ala540Glu	missense_variant	Exon 12 of 29	1	NM_004646.4	ENSP00000368190.4		O60500-1
NPHS1	ENST00000353632.6 link	c.1619C>A	p.Ala540Glu	missense_variant	Exon 12 of 28	5		ENSP00000343634.5		O60500-2

Frequencies

GnomAD3 genomes

AF:

0.000492

AC:

AN:

146490

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000348

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000869

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000323

AC:

AN:

194768

Hom.:

AF XY:

0.000295

AC XY:

AN XY:

104982

show subpopulations

Gnomad AFR exome

AF:

0.000616

Gnomad AMR exome

AF:

0.0000346

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:

0.000638

Gnomad OTH exome

AF:

0.000392

GnomAD4 exome

AF:

0.00101

AC:

1283

AN:

1275776

Hom.:

Cov.:

AF XY:

0.000895

AC XY:

565

AN XY:

631044

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000278

Gnomad4 NFE exome

AF:

0.00125

Gnomad4 OTH exome

AF:

0.000451

GnomAD4 genome

AF:

0.000492

AC:

AN:

146490

Hom.:

Cov.:

AF XY:

0.000448

AC XY:

AN XY:

71472

show subpopulations

Gnomad4 AFR

AF:

0.000348

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000869

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000743

Hom.:

Bravo

AF:

0.000434

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000815

AC:

ExAC

AF:

0.000141

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 22, 2021

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Finnish congenital nephrotic syndrome

Uncertain:1Benign:1

Feb 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 05, 2019

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

NPHS1-related disorder

Uncertain:1

Feb 22, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NPHS1 c.1619C>A variant is predicted to result in the amino acid substitution p.Ala540Glu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.068% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Congenital nephrotic syndrome

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled 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

0.11

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.74

DEOGEN2

Benign

0.20

T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.57

T;T

M_CAP

Benign

0.085

MetaRNN

Benign

0.030

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.0

N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.62

N;N

REVEL

Benign

0.15

Sift

Benign

0.88

T;T

Sift4G

Benign

0.37

T;T

Polyphen

0.079

B;.

Vest4

0.19

MVP

0.52

MPC

0.20

ClinPred

0.0067

GERP RS

-0.16

Varity_R

0.081

gMVP

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.75

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.75

Position offset: -1

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