1-179559734-T-C

Position:

• chr1-179559734-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_014625.4(NPHS2):​c.479A>G​(p.Asp160Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D160V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NPHS2 NM_014625.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.00

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 259) in uniprot entity PODO_HUMAN there are 130 pathogenic changes around while only 3 benign (98%) in NM_014625.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-179559734-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 599118.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 1-179559734-T-C is Pathogenic according to our data. Variant chr1-179559734-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 5367.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-179559734-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHS2	NM_014625.4	c.479A>G	p.Asp160Gly	missense_variant	4/8	ENST00000367615.9	NP_055440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHS2	ENST00000367615.9	c.479A>G	p.Asp160Gly	missense_variant	4/8	1	NM_014625.4	ENSP00000356587.4
NPHS2	ENST00000367616.4	c.479A>G	p.Asp160Gly	missense_variant	4/7	1		ENSP00000356588.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Nephrotic syndrome, type 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2000

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.6	H;H
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.5	D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.97
MutPred		0.88		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.95
MPC		1.1
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.97
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs74315346; hg19: chr1-179528869;