rs1490010141

Variant names:

• chr1-179552614-C-T
• rs1490010141
• NM_014625.4:c.862G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_014625.4(NPHS2):​c.862G>A​(p.Ala288Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,406 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NPHS2 NM_014625.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 5.66
• Publications: 5 publications found

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]

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

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_014625.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 0.68612 (below the threshold of 3.09). Trascript score misZ: 0.038296 (below the threshold of 3.09). GenCC associations: The gene is linked to nephrotic syndrome, type 2, familial idiopathic steroid-resistant nephrotic syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963
• PP5: Variant 1-179552614-C-T is Pathogenic according to our data. Variant chr1-179552614-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 556281.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHS2	NM_014625.4	c.862G>A	p.Ala288Thr	missense_variant	Exon 7 of 8	ENST00000367615.9	NP_055440.1
AXDND1	NM_144696.6	c.3032-1898C>T		intron_variant	Intron 25 of 25	ENST00000367618.8	NP_653297.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHS2	ENST00000367615.9	c.862G>A	p.Ala288Thr	missense_variant	Exon 7 of 8	1	NM_014625.4	ENSP00000356587.4
AXDND1	ENST00000367618.8	c.3032-1898C>T		intron_variant	Intron 25 of 25	1	NM_144696.6	ENSP00000356590.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250138 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461406 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726990

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111830

Other (OTH) AF: 0.00 AC: 0 AN: 60354

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3 Uncertain:1

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 288 of the NPHS2 protein (p.Ala288Thr). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of steroid-resistant nephrotic syndrome (PMID: 12464671, 19145239, 21415313, 24509478). 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: 556281). 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. -

May 16, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 21415313, 29660491, 24509478, 25349199, 20947785, 30260545, Behnam2016[paper], 24072147, 33102883, 15253708, 19145239, 12464671) -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nephrotic syndrome, type 2 Pathogenic:2

Jul 26, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 23, 2018

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.84	T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Uncertain	2.7	M;.
PhyloP100		5.7
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0050	D;T
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;D
Vest4		0.88
MutPred		0.84		Gain of phosphorylation at A288 (P = 0.0427);.;
MVP		0.91
MPC		0.90
ClinPred		0.96	D
GERP RS		5.3
Varity_R		0.70
gMVP		0.73
Mutation Taster		=17/83	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: 18

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1490010141; hg19: chr1-179521749;