rs1490010141

Positions:

• chr1-179552614-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 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

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

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 259) in uniprot entity PODO_HUMAN there are 94 pathogenic changes around while only 1 benign (99%) in NM_014625.4
• PM2: Very rare variant in population databases, with high coverage
• 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 id is 556281.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=2}. Variant chr1-179552614-C-T is described in Lovd as [Pathogenic]. Variant chr1-179552614-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHS2	ENST00000367615.9	c.862G>A	p.Ala288Thr	missense_variant	7/8	1	NM_014625.4	ENSP00000356587	P1
AXDND1	ENST00000367618.8	c.3032-1898C>T		intron_variant		1	NM_144696.6	ENSP00000356590	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250138 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135246

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: 0.00000885

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

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 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

Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 11, 2023	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. -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2022	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) -

Nephrotic syndrome, type 2 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 26, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 23, 2018	- -

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;.
MutationTaster	Benign	1.0	D;D;D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1490010141; hg19: chr1-179521749;