rs392702

Variant names:

• chr19-35848161-G-A
• rs392702
• NM_004646.4:c.1320C>T

Variant summary

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

The NM_004646.4(NPHS1):​c.1320C>T​(p.Pro440Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0431 in 1,613,988 control chromosomes in the GnomAD database, including 2,819 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.085 (1072 hom., cov: 32)
  • Exomes 𝑓: 0.039 (1747 hom.)
• Consequence: NPHS1 NM_004646.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.40
• Publications: 10 publications found

Genes affected

NPHS1 (HGNC:7908): (NPHS1 adhesion molecule, nephrin) This gene encodes a member of the immunoglobulin family of cell adhesion molecules that functions in the glomerular filtration barrier in the kidney. The gene is primarily expressed in renal tissues, and the protein is a type-1 transmembrane protein found at the slit diaphragm of glomerular podocytes. The slit diaphragm is thought to function as an ultrafilter to exclude albumin and other plasma macromolecules in the formation of urine. Mutations in this gene result in Finnish-type congenital nephrosis 1, characterized by severe proteinuria and loss of the slit diaphragm and foot processes.[provided by RefSeq, Oct 2009]

NPHS1 Gene-Disease associations (from GenCC):

• congenital nephrotic syndrome, Finnish type

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 19-35848161-G-A is Benign according to our data. Variant chr19-35848161-G-A is described in ClinVar as Benign. ClinVar VariationId is 259484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.4 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.212 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHS1	NM_004646.4	c.1320C>T	p.Pro440Pro	synonymous_variant	Exon 11 of 29	ENST00000378910.10	NP_004637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHS1	ENST00000378910.10	c.1320C>T	p.Pro440Pro	synonymous_variant	Exon 11 of 29	1	NM_004646.4	ENSP00000368190.4
NPHS1	ENST00000353632.6	c.1320C>T	p.Pro440Pro	synonymous_variant	Exon 11 of 28	5		ENSP00000343634.5
NPHS1	ENST00000592132.1	n.327C>T		non_coding_transcript_exon_variant	Exon 4 of 4	3

Frequencies

GnomAD3 genomes AF: 0.0852 AC: 12957 AN: 152136 Hom.: 1070 Cov.: 32

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0482

Gnomad ASJ AF: 0.0430

Gnomad EAS AF: 0.00596

Gnomad SAS AF: 0.0462

Gnomad FIN AF: 0.0408

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0327

Gnomad OTH AF: 0.0774

GnomAD2 exomes AF: 0.0455 AC: 11400 AN: 250822 AF XY: 0.0433

Gnomad AFR exome AF: 0.219

Gnomad AMR exome AF: 0.0229

Gnomad ASJ exome AF: 0.0467

Gnomad EAS exome AF: 0.00561

Gnomad FIN exome AF: 0.0418

Gnomad NFE exome AF: 0.0333

Gnomad OTH exome AF: 0.0390

GnomAD4 exome AF: 0.0387 AC: 56572 AN: 1461734 Hom.: 1747 Cov.: 31 AF XY: 0.0384 AC XY: 27906 AN XY: 727174

African (AFR) AF: 0.217 AC: 7277 AN: 33480

American (AMR) AF: 0.0272 AC: 1217 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0464 AC: 1212 AN: 26136

East Asian (EAS) AF: 0.00390 AC: 155 AN: 39698

South Asian (SAS) AF: 0.0499 AC: 4302 AN: 86256

European-Finnish (FIN) AF: 0.0428 AC: 2283 AN: 53288

Middle Eastern (MID) AF: 0.0402 AC: 232 AN: 5768

European-Non Finnish (NFE) AF: 0.0334 AC: 37143 AN: 1111992

Other (OTH) AF: 0.0456 AC: 2751 AN: 60392

GnomAD4 genome AF: 0.0853 AC: 12982 AN: 152254 Hom.: 1072 Cov.: 32 AF XY: 0.0839 AC XY: 6247 AN XY: 74456

African (AFR) AF: 0.216 AC: 8974 AN: 41504

American (AMR) AF: 0.0481 AC: 736 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0430 AC: 149 AN: 3468

East Asian (EAS) AF: 0.00598 AC: 31 AN: 5188

South Asian (SAS) AF: 0.0466 AC: 225 AN: 4824

European-Finnish (FIN) AF: 0.0408 AC: 433 AN: 10620

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0327 AC: 2224 AN: 68030

Other (OTH) AF: 0.0766 AC: 162 AN: 2116

Alfa AF: 0.0508 Hom.: 619

Bravo AF: 0.0913

Asia WGS AF: 0.0420 AC: 148 AN: 3478

EpiCase AF: 0.0315

EpiControl AF: 0.0375

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Finnish congenital nephrotic syndrome Benign:3

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 15, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital nephrotic syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	2.5
DANN	Benign	0.71
PhyloP100		-1.4
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: rs392702; hg19: chr19-36339063;