rs2285450

Positions:

chr19-35851365-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004646.4(NPHS1):c.294C>T(p.Ile98Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,613,202 control chromosomes in the GnomAD database, including 1,183 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.041 ( 365 hom., cov: 32)

Exomes 𝑓: 0.0095 ( 818 hom. )

Consequence

NPHS1
NM_004646.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.365

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:18816): (kirre like nephrin family adhesion molecule 2) This gene encodes a type I transmembrane protein and member of the immunoglobulin superfamily of cell adhesion molecules. The encoded protein localizes to adherens junctions in pancreatic beta cells and regulates insulin secretion. Autoantibodies against the encoded protein have been detected in serum from patients with type 1 diabetes. This gene may also play a role in glomerular development and decreased expression of this gene has been observed in human glomerular diseases. This gene and the related opposite-strand gene nephrin (GeneID: 527362) are regulated by a bidirectional promoter. [provided by RefSeq, Jul 2016]

KIRREL2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 19-35851365-G-A is Benign according to our data. Variant chr19-35851365-G-A is described in ClinVar as [Benign]. Clinvar id is 259492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-35851365-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.365 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.125 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.294C>T	p.Ile98Ile	synonymous_variant	3/29	ENST00000378910.10	NP_004637.1	O60500-1
KIRREL2	XM_011527362.2 linkuse as main transcript	c.-542G>A		upstream_gene_variant			XP_011525664.1	Q6UWL6-1
KIRREL2	XM_011527363.2 linkuse as main transcript	c.-533G>A		upstream_gene_variant			XP_011525665.1	Q6UWL6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHS1	ENST00000378910.10 linkuse as main transcript	c.294C>T	p.Ile98Ile	synonymous_variant	3/29	1	NM_004646.4	ENSP00000368190.4		O60500-1
NPHS1	ENST00000353632.6 linkuse as main transcript	c.294C>T	p.Ile98Ile	synonymous_variant	3/28	5		ENSP00000343634.5		O60500-2

Frequencies

GnomAD3 genomes

AF:

0.0408

AC:

6201

AN:

152132

Hom.:

345

Cov.:

show subpopulations

Gnomad AFR

AF:

0.121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0172

Gnomad ASJ

AF:

0.0109

Gnomad EAS

AF:

0.134

Gnomad SAS

AF:

0.0186

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000691

Gnomad OTH

AF:

0.0229

GnomAD3 exomes

AF:

0.0217

AC:

5349

AN:

246642

Hom.:

318

AF XY:

0.0190

AC XY:

2544

AN XY:

133884

show subpopulations

Gnomad AFR exome

AF:

0.128

Gnomad AMR exome

AF:

0.00680

Gnomad ASJ exome

AF:

0.0136

Gnomad EAS exome

AF:

0.133

Gnomad SAS exome

AF:

0.0124

Gnomad FIN exome

AF:

0.000284

Gnomad NFE exome

AF:

0.000911

Gnomad OTH exome

AF:

0.0122

GnomAD4 exome

AF:

0.00949

AC:

13861

AN:

1460952

Hom.:

818

Cov.:

AF XY:

0.00911

AC XY:

6624

AN XY:

726750

show subpopulations

Gnomad4 AFR exome

AF:

0.133

Gnomad4 AMR exome

AF:

0.00738

Gnomad4 ASJ exome

AF:

0.0130

Gnomad4 EAS exome

AF:

0.148

Gnomad4 SAS exome

AF:

0.0130

Gnomad4 FIN exome

AF:

0.000244

Gnomad4 NFE exome

AF:

0.000486

Gnomad4 OTH exome

AF:

0.0183

GnomAD4 genome

AF:

0.0411

AC:

6250

AN:

152250

Hom.:

365

Cov.:

AF XY:

0.0409

AC XY:

3043

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.122

Gnomad4 AMR

AF:

0.0172

Gnomad4 ASJ

AF:

0.0109

Gnomad4 EAS

AF:

0.134

Gnomad4 SAS

AF:

0.0180

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.000691

Gnomad4 OTH

AF:

0.0222

Alfa

AF:

0.0201

Hom.:

Bravo

AF:

0.0472

Asia WGS

AF:

0.0640

AC:

221

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 23, 2019	This variant is associated with the following publications: (PMID: 26147534) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Finnish congenital nephrotic syndrome

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 25, 2019

- -

Congenital nephrotic syndrome

Benign:1

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

7.6

DANN

Benign

0.91

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