rs1477180313

Variant names:

• chr1-179575777-C-A
• rs1477180313
• NM_014625.4:c.88G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-179575777-C-A
• chr1-179575777-C-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_014625.4(NPHS2):​c.88G>T​(p.Glu30*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000743 in 1,345,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E30E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: NPHS2 NM_014625.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.48
• Publications: 0 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]

NPHS2 Gene-Disease associations (from GenCC):

• nephrotic syndrome, type 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Myriad Women’s Health, Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina, G2P
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 123 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHS2	NM_014625.4	c.88G>T	p.Glu30*	stop_gained	Exon 1 of 8	ENST00000367615.9	NP_055440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHS2	ENST00000367615.9	c.88G>T	p.Glu30*	stop_gained	Exon 1 of 8	1	NM_014625.4	ENSP00000356587.4
NPHS2	ENST00000367616.4	c.88G>T	p.Glu30*	stop_gained	Exon 1 of 7	1		ENSP00000356588.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.43e-7 AC: 1 AN: 1345468 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 664044

African (AFR) AF: 0.00 AC: 0 AN: 27650

American (AMR) AF: 0.00 AC: 0 AN: 28522

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23114

East Asian (EAS) AF: 0.00 AC: 0 AN: 32480

South Asian (SAS) AF: 0.00 AC: 0 AN: 73414

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39232

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5334

European-Non Finnish (NFE) AF: 9.43e-7 AC: 1 AN: 1059960

Other (OTH) AF: 0.00 AC: 0 AN: 55762

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Benign	-0.0032
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.12	N
PhyloP100		1.5
Vest4		0.53
GERP RS		1.8
PromoterAI		0.060	Neutral
Mutation Taster		=4/196	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1477180313; hg19: chr1-179544912;