rs3818587

Variant names:

• chr1-179551287-T-C
• rs3818587
• NM_014625.4:c.1038A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014625.4(NPHS2):​c.1038A>G​(p.Leu346Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0845 in 1,613,852 control chromosomes in the GnomAD database, including 6,329 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 (610 hom., cov: 32)
  • Exomes 𝑓: 0.085 (5719 hom.)
• Consequence: NPHS2 NM_014625.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0750
• Publications: 23 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 1-179551287-T-C is Benign according to our data. Variant chr1-179551287-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.075 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0867 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHS2	NM_014625.4	c.1038A>G	p.Leu346Leu	synonymous_variant	Exon 8 of 8	ENST00000367615.9	NP_055440.1
AXDND1	NM_144696.6	c.3032-3225T>C		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.1038A>G	p.Leu346Leu	synonymous_variant	Exon 8 of 8	1	NM_014625.4	ENSP00000356587.4
AXDND1	ENST00000367618.8	c.3032-3225T>C		intron_variant	Intron 25 of 25	1	NM_144696.6	ENSP00000356590.3

Frequencies

GnomAD3 genomes AF: 0.0845 AC: 12833 AN: 151884 Hom.: 610 Cov.: 32

Gnomad AFR AF: 0.0892

Gnomad AMI AF: 0.112

Gnomad AMR AF: 0.0594

Gnomad ASJ AF: 0.0746

Gnomad EAS AF: 0.0888

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0854

Gnomad OTH AF: 0.0796

GnomAD2 exomes AF: 0.0735 AC: 18453 AN: 251196 AF XY: 0.0706

Gnomad AFR exome AF: 0.0904

Gnomad AMR exome AF: 0.0355

Gnomad ASJ exome AF: 0.0633

Gnomad EAS exome AF: 0.0938

Gnomad FIN exome AF: 0.131

Gnomad NFE exome AF: 0.0851

Gnomad OTH exome AF: 0.0767

GnomAD4 exome AF: 0.0845 AC: 123590 AN: 1461850 Hom.: 5719 Cov.: 46 AF XY: 0.0818 AC XY: 59517 AN XY: 727226

African (AFR) AF: 0.0860 AC: 2878 AN: 33480

American (AMR) AF: 0.0376 AC: 1681 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0645 AC: 1686 AN: 26132

East Asian (EAS) AF: 0.0673 AC: 2673 AN: 39700

South Asian (SAS) AF: 0.0137 AC: 1182 AN: 86258

European-Finnish (FIN) AF: 0.131 AC: 6988 AN: 53420

Middle Eastern (MID) AF: 0.0139 AC: 80 AN: 5766

European-Non Finnish (NFE) AF: 0.0912 AC: 101403 AN: 1111980

Other (OTH) AF: 0.0831 AC: 5019 AN: 60394

GnomAD4 genome AF: 0.0845 AC: 12841 AN: 152002 Hom.: 610 Cov.: 32 AF XY: 0.0837 AC XY: 6218 AN XY: 74304

African (AFR) AF: 0.0891 AC: 3694 AN: 41444

American (AMR) AF: 0.0593 AC: 905 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.0746 AC: 259 AN: 3472

East Asian (EAS) AF: 0.0890 AC: 459 AN: 5158

South Asian (SAS) AF: 0.0139 AC: 67 AN: 4810

European-Finnish (FIN) AF: 0.130 AC: 1379 AN: 10584

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0854 AC: 5802 AN: 67966

Other (OTH) AF: 0.0792 AC: 167 AN: 2108

Alfa AF: 0.0803 Hom.: 886

Bravo AF: 0.0800

Asia WGS AF: 0.0390 AC: 136 AN: 3478

EpiCase AF: 0.0768

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

Nov 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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	5.0
DANN	Benign	0.55
PhyloP100		-0.075
Mutation Taster		=100/0	polymorphism (auto)

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: rs3818587; hg19: chr1-179520422; COSMIC: COSV62635449; COSMIC: COSV62635449;