rs1291398331

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_014625.4(NPHS2):c.535-1G>T variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000186 in 1,613,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

NPHS2
NM_014625.4 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 4.52

Variant links:

Genes affected

NPHS2 (HGNC:13394): (NPHS2 stomatin family member, podocin) This gene encodes a protein that plays a role in the regulation of glomerular permeability. Mutations in this gene cause steroid-resistant nephrotic syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

NPHS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.17708333 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.3, offset of -49, new splice context is: gttcctctaaccccacatAGgaa. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-179557231-C-A is Pathogenic according to our data. Variant chr1-179557231-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 504890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-179557231-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHS2	NM_014625.4 link	c.535-1G>T		splice_acceptor_variant, intron_variant	Intron 4 of 7	ENST00000367615.9	NP_055440.1	Q9NP85-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHS2	ENST00000367615.9 link	c.535-1G>T		splice_acceptor_variant, intron_variant	Intron 4 of 7	1	NM_014625.4	ENSP00000356587.4		Q9NP85-1
NPHS2	ENST00000367616.4 link	c.534+2448G>T		intron_variant	Intron 4 of 6	1		ENSP00000356588.4		Q9NP85-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461542

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727078

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Nephrotic syndrome, type 2

Pathogenic:3

Apr 11, 2023

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 09, 2017

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 22, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial idiopathic steroid-resistant nephrotic syndrome

Pathogenic:1

Feb 19, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.535-1G>T variant in NPHS2 has been reported in 2 individuals with steroid- resistant nephrotic syndrome, one of whom was homozygous and one was compound he terozygous (Karle 2002, Hocker 2006). This variant was absent from large populat ion studies. This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abn ormal or absent protein. Loss of function of the NPHS2 gene is associated with i diopathic steroid-resistant nephrotic syndrome. In summary, this variant meets o ur criteria to be classified as pathogenic for idiopathic steroid-resistant neph rotic syndrome in an autosomal recessive manner. -

Steroid-resistant nephrotic syndrome

Pathogenic:1

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

NPHS2-related disorder

Pathogenic:1

Sep 27, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NPHS2 c.535-1G>T variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant was reported in the homozygous state or with a pathogenic variant in individuals with steroid resistant nephrotic syndrome (Karle et al. 2002. PubMed ID: 11805166; Supplementary Table 1, Zhu et al. 2022. PubMed ID: 35755072). This variant has not been reported in a large population database, indicating this variant is rare. Variants that disrupt the consensus splice acceptor site in NPHS2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Idiopathic nephrotic syndrome

Pathogenic:1

Aug 19, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: NPHS2 c.535-1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250718 control chromosomes (gnomAD). c.535-1G>T has been reported in the literature as a biallelic genotype in individuals affected with Steroid Resistant Nephrotic Syndrome (e.g. Karle_2002, Hocker_2006). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters have assessed the variant since 2014: all three classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

0.98

GERP RS

5.5

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.92

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.37

Position offset: 48

DS_AL_spliceai

0.92

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