rs3738423

Variant names:

• chr1-179564780-G-A
• rs3738423
• NM_014625.4:c.288C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014625.4(NPHS2):​c.288C>T​(p.Ser96Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0842 in 1,612,474 control chromosomes in the GnomAD database, including 6,307 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.084 (615 hom., cov: 32)
  • Exomes 𝑓: 0.084 (5692 hom.)
• Consequence: NPHS2 NM_014625.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.42

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 1-179564780-G-A is Benign according to our data. Variant chr1-179564780-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 260426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-179564780-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.42 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0857 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHS2	NM_014625.4	c.288C>T	p.Ser96Ser	synonymous_variant	Exon 2 of 8	ENST00000367615.9	NP_055440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHS2	ENST00000367615.9	c.288C>T	p.Ser96Ser	synonymous_variant	Exon 2 of 8	1	NM_014625.4	ENSP00000356587.4
NPHS2	ENST00000367616.4	c.288C>T	p.Ser96Ser	synonymous_variant	Exon 2 of 7	1		ENSP00000356588.4

Frequencies

GnomAD3 genomes AF: 0.0841 AC: 12797 AN: 152076 Hom.: 615 Cov.: 32

Gnomad AFR AF: 0.0882

Gnomad AMI AF: 0.112

Gnomad AMR AF: 0.0596

Gnomad ASJ AF: 0.0747

Gnomad EAS AF: 0.0889

Gnomad SAS AF: 0.0139

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0852

Gnomad OTH AF: 0.0784

GnomAD3 exomes AF: 0.0734 AC: 18446 AN: 251188 Hom.: 904 AF XY: 0.0706 AC XY: 9582 AN XY: 135780

Gnomad AFR exome AF: 0.0896

Gnomad AMR exome AF: 0.0355

Gnomad ASJ exome AF: 0.0634

Gnomad EAS exome AF: 0.0939

Gnomad SAS exome AF: 0.0144

Gnomad FIN exome AF: 0.131

Gnomad NFE exome AF: 0.0851

Gnomad OTH exome AF: 0.0760

GnomAD4 exome AF: 0.0842 AC: 122921 AN: 1460280 Hom.: 5692 Cov.: 31 AF XY: 0.0815 AC XY: 59206 AN XY: 726504

Gnomad4 AFR exome AF: 0.0846

Gnomad4 AMR exome AF: 0.0375

Gnomad4 ASJ exome AF: 0.0644

Gnomad4 EAS exome AF: 0.0675

Gnomad4 SAS exome AF: 0.0138

Gnomad4 FIN exome AF: 0.131

Gnomad4 NFE exome AF: 0.0908

Gnomad4 OTH exome AF: 0.0825

GnomAD4 genome AF: 0.0841 AC: 12803 AN: 152194 Hom.: 615 Cov.: 32 AF XY: 0.0832 AC XY: 6191 AN XY: 74416

Gnomad4 AFR AF: 0.0881

Gnomad4 AMR AF: 0.0595

Gnomad4 ASJ AF: 0.0747

Gnomad4 EAS AF: 0.0891

Gnomad4 SAS AF: 0.0137

Gnomad4 FIN AF: 0.131

Gnomad4 NFE AF: 0.0852

Gnomad4 OTH AF: 0.0781

Alfa AF: 0.0800 Hom.: 402

Bravo AF: 0.0798

Asia WGS AF: 0.0380 AC: 133 AN: 3478

EpiCase AF: 0.0764

EpiControl AF: 0.0756

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nephrotic syndrome, type 2 Benign:3

Apr 29, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Apr 11, 2023

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 06, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Steroid-resistant nephrotic syndrome Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.3
DANN	Benign	0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs3738423; hg19: chr1-179533915; COSMIC: COSV62635462;