rs780761368

Positions:

chr1-179552625-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_014625.4(NPHS2):c.851C>T(p.Ala284Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000744 in 1,613,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A284A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

NPHS2
NM_014625.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 5.46

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:

AXDND1 (HGNC:26564): (axonemal dynein light chain domain containing 1)

AXDND1 links:

AXDND1 (HGNC:):

AXDND1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in NM_014625.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

PP5

Variant 1-179552625-G-A is Pathogenic according to our data. Variant chr1-179552625-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 562398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-179552625-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHS2	NM_014625.4 linkuse as main transcript	c.851C>T	p.Ala284Val	missense_variant	7/8	ENST00000367615.9	NP_055440.1	Q9NP85-1
AXDND1	NM_144696.6 linkuse as main transcript	c.3032-1887G>A		intron_variant		ENST00000367618.8	NP_653297.3	Q5T1B0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHS2	ENST00000367615.9 linkuse as main transcript	c.851C>T	p.Ala284Val	missense_variant	7/8	1	NM_014625.4	ENSP00000356587.4		Q9NP85-1
AXDND1	ENST00000367618.8 linkuse as main transcript	c.3032-1887G>A		intron_variant		1	NM_144696.6	ENSP00000356590.3		Q5T1B0-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

249998

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135218

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1461466

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727032

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000557

Hom.:

Bravo

AF:

0.0000793

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Nephrotic syndrome, type 2

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 25, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Jun 03, 2019	This missense varaint (c.851C>T, p.Ala284Val) has not been observed in population databases (gnomAD) but has been reported in the literature (PMID 20947785, 26455708, others). Variant prediction programs suggest a deleterious effect, although no functional studies have been reported. This change was identified in an affected patient. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 30, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 09, 2023	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 284 of the NPHS2 protein (p.Ala284Val). This variant is present in population databases (rs780761368, gnomAD 0.0009%). This missense change has been observed in individuals with clinical features of steroid-resistant nephrotic syndrome (PMID: 11805166, 16354237, 18823551, 23349334, 23515051, 29982877). It has been reported in trans with the variant p.Arg229Gln in related affected individuals. This suggests that the combination of p.Arg229Gln and this variant may be clinically significant. ClinVar contains an entry for this variant (Variation ID: 562398). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NPHS2 protein function with a positive predictive value of 80%. This variant has been shown to alter NPHS2 (podocin) protein function, resulting in podocin mislocalization when in combination with p.Arg229Gln-podocin (PMID: 24509478). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 07, 2025	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35325889, 37217505, 31308072, 24509478, 21415313, 26211502, 16354237, 16898497, 26420286, 29982877, 32604935, 11805166, 23515051, 23349334, 19876656, 21355056, 19145239, 14978175, 12464671, 15253708, 18823551, 30586318, 35253369, 38765578, 37850020, 37547535, 26455708) -
Pathogenic, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 11, 2021	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. The variant is located in a region that is considered important for protein function and/or structure. -

Idiopathic nephrotic syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Mar 10, 2022

Variant summary: NPHS2 c.851C>T (p.Ala284Val) results in a non-conservative amino acid change located in the Band 7 domain (IPR001107) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 150926 control chromosomes (gnomAD v3.1, genomes dataset). The variant, c.851C>T, has been reported in the literature in multiple homozygous individuals affected with Nephrotic Syndrome Type 2, which progressed to end-stage renal disease (e.g. Tsukaguchi_2002, Karle_2002, Kitzler_2018). This variant was also reported in compound heterozygous state in numerous patients with a well-reported, frequent, genotype-dependent risk variant p.R229Q (e.g. Tsukaguchi_2002, Machuca_2009, Santin_2011), and occasionally also with other (potentially) pathogenic variants in trans (e.g. Park_2020). These data indicate that the variant is very likely to be associated with disease. An extensive study performed by Tory_2014, demonstrated that the A284V podocin protein was mislocalized in the cytoplasmic compartment (either when coexpressed with the WT or with the R229Q podocin), in contrast, while WT podocin reached the plasma membrane, podocin R229Q was retained in the cytoplasm in cells coexpressing podocin A284V (on the other hand, both the WT podocin and podocin R229Q were localized to the plasma membrane when coexpressed together); authors concluded that these interactions mimicked a dominant-negative effect of A284V on the R229Q variant protein. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic (n=3) / likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

D;.

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

0.89

MutationAssessor

Pathogenic

3.8

H;.

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.8

D;D

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0010

D;T

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.94

MutPred

0.94

Loss of disorder (P = 0.0728);.;

MVP

0.93

MPC

0.91

ClinPred

1.0

GERP RS

5.3

Varity_R

0.86

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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