chr1-179551435-G-A

Position:

chr1-179551435-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The ENST00000367615.9(NPHS2):c.890C>T(p.Ala297Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,613,320 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. A297A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

NPHS2
ENST00000367615.9 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.77

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in ENST00000367615.9

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.886

PP5

Variant 1-179551435-G-A is Pathogenic according to our data. Variant chr1-179551435-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-179551435-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.890C>T	p.Ala297Val	missense_variant	8/8	ENST00000367615.9	NP_055440.1
AXDND1	NM_144696.6 linkuse as main transcript	c.3032-3077G>A		intron_variant		ENST00000367618.8	NP_653297.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHS2	ENST00000367615.9 linkuse as main transcript	c.890C>T	p.Ala297Val	missense_variant	8/8	1	NM_014625.4	ENSP00000356587	P1	Q9NP85-1
AXDND1	ENST00000367618.8 linkuse as main transcript	c.3032-3077G>A		intron_variant		1	NM_144696.6	ENSP00000356590	P2	Q5T1B0-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250734

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135464

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461156

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726892

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.0000724

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000138

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.00000824

AC:

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

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Aug 02, 2022	The NPHS2 c.890C>T variant is classified as LIKELY PATHOGENIC (PS4_Moderate, PS3, PM2, PP3) The NPHS2 c.890C>T variant is a single nucleotide change in exon 8/8 of the NPHS2 gene, which is predicted to change the amino acid alanine at position 297 in the protein to valine. The variant is rare in population databases (PM2) and has been reported in at least 4 probands with a clinical presentation of focal segmental glomerulosclerosis (HGMD – CM023109) (PS4_Moderate). Transfection studies in human podocyte cell lines showed that when the p.Ala297Val variant was co-expressed with p.Arg229Gln (also in this patient), podocin was retained in the cytoplasm, rather than localising properly to the plasma membrane (Tory et al. 2014 PMID:24509478) (PS3). Computational structural modelling showed the p.Ala297Val variant in trans with p.Arg229Gln led to altered dimerisation. They predicted this most likely contributed to the retention of podocin within cytoplasmic compartments. Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs199506378) and in the HGMD database: CM023109. It has been reported as pathogenicy by other diagnostic laboratories (ClinVar Variation ID: 370718). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 22, 2016	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2023

The c.890C>T (p.A297V) alteration is located in exon 8 (coding exon 8) of the NPHS2 gene. This alteration results from a C to T substitution at nucleotide position 890, causing the alanine (A) at amino acid position 297 to be replaced by a valine (V). Based on data from gnomAD, the T allele has an overall frequency of 0.001% (2/282136) total alleles studied. The highest observed frequency was 0.008% (2/24964) of African alleles. This alteration has been reported in trans with a second NPHS2 alteration in multiple individuals with clinical features consistent with NPHS2-related nephrotic syndrome (Tsukaguchi, 2002; Caridi, 2003; Machuca, 2009; Lipska, 2013; Phelan, 2015; Sen, 2017; Jyoti, 2020). This amino acid position is poorly conserved in available vertebrate species. Functional analysis suggests that when associated with p.R229Q podocin, the p.A297V alteration has a dominant-negative effect leading to p.R229Q podocin being retained in the cytoplasm. When the p.A297V alteration is associated with wildtype podocin, p.A297V behaves as a recessive alteration (Tory, 2014). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 06, 2023

For these reasons, this variant has been classified as Pathogenic. This variant has been shown to alter NPHS2 (podocin) protein function, resulting in podocin mislocalization when in combination with p.Arg229Gln-podocin (PMID: 24509478). 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 not expected to disrupt NPHS2 protein function. ClinVar contains an entry for this variant (Variation ID: 370718). This missense change has been observed in individual(s) with clinical features of steroid-resistant nephrotic syndrome (PMID: 12464671, 12707396, 19145239, 24509478, 26413278, 28780565). 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. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 297 of the NPHS2 protein (p.Ala297Val). -

Nephrotic syndrome

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Sydney Genome Diagnostics, Children's Hospital Westmead

Oct 19, 2018

This individual is heterozygous for a known pathogenic variant, c.890C>T, in the NPHS2 gene which results in an amino acid substitution of alanine to valine at residue 297, p.(Ala297Val). This variant has been reported in the gnomAD browser (http://gnomad.broadinstitute.org) with a very low allele frequency (1 out of 245,474 alleles). This variant has been previously described in multiple patients with nephrotic sydrome and has also been reported in trans with the c.686G>A variant also identified in this individual (Phelan et al 2015 Clin Kidney J 8: 538-554). Functional studies of the p.Ala297Val mutant protein, co-expressed with the p.Arg229Gln mutant, supported a detrimental effect on protein function (Tory et al 2014 Nat Genet 46: 299-304). This variant is considered to be pathogenic according to the ACMG guidelines (evidence used: PS3, PM2, PM3). -

Idiopathic nephrotic syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Jun 27, 2022

Variant summary: NPHS2 c.890C>T (p.Ala297Val) results in a non-conservative amino acid change located in the Band 7 domain (IPR001107) of the encoded protein sequence. Four 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-06 in 250734 control chromosomes. c.890C>T has been reported in the literature as a compound heterozygous genotype with the NPHS2 p.R229Q variant in individuals affected with features of steroid-resistant nephrotic syndrome (SRNS)/focal and segmental glomerulosclerosis (FSGS) (example, Machuca_2009, Tsukaguchi_2002, Buscher_2010, Sen_2017, Lipska_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported, although colocalization of truncated podocin variants with an intact H1 domain was strongly influenced by A297V. A dispersed reticular localization when coexpressed with A297V similar to R229Q-A297V association (Straner_2018). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

D;.

Eigen

Benign

0.037

Eigen_PC

Benign

0.16

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.93

D;D

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.89

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.2

L;.

MutationTaster

Benign

1.0

D;D;N

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-2.9

D;D

REVEL

Pathogenic

0.78

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

0.68

P;B

Vest4

0.74

MutPred

0.89

Loss of disorder (P = 0.0502);.;

MVP

0.86

MPC

0.45

ClinPred

0.95

GERP RS

5.7

Varity_R

0.60

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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