rs2073901

chr19-35843583-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_004646.4(NPHS1):c.2223C>T(p.Thr741=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00358 in 1,614,032 control chromosomes in the GnomAD database, including 156 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (145 hom.)
• Consequence: NPHS1 NM_004646.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.687

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 19-35843583-G-A is Benign according to our data. Variant chr19-35843583-G-A is described in ClinVar as [Benign]. Clinvar id is 259488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-35843583-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0519 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHS1	NM_004646.4	c.2223C>T	p.Thr741=	synonymous_variant	17/29	ENST00000378910.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHS1	ENST00000378910.10	c.2223C>T	p.Thr741=	synonymous_variant	17/29	1	NM_004646.4	P2
NPHS1	ENST00000585400.1	n.914C>T		non_coding_transcript_exon_variant	3/3	1
NPHS1	ENST00000353632.6	c.2223C>T	p.Thr741=	synonymous_variant	17/28	5		A2

Frequencies

GnomAD3 genomes AF: 0.00514 AC: 783 AN: 152224 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00813

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.0573

Gnomad SAS AF: 0.0143

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00673 AC: 1693 AN: 251440 Hom.: 39 AF XY: 0.00675 AC XY: 917 AN XY: 135900

Gnomad AFR exome AF: 0.00671

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00823

Gnomad EAS exome AF: 0.0580

Gnomad SAS exome AF: 0.0106

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.000466

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00342 AC: 5000 AN: 1461690 Hom.: 145 Cov.: 31 AF XY: 0.00361 AC XY: 2627 AN XY: 727136

Gnomad4 AFR exome AF: 0.00860

Gnomad4 AMR exome AF: 0.000671

Gnomad4 ASJ exome AF: 0.00746

Gnomad4 EAS exome AF: 0.0733

Gnomad4 SAS exome AF: 0.0108

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.000323

Gnomad4 OTH exome AF: 0.00417

GnomAD4 genome AF: 0.00513 AC: 781 AN: 152342 Hom.: 11 Cov.: 32 AF XY: 0.00515 AC XY: 384 AN XY: 74492

Gnomad4 AFR AF: 0.00810

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.0572

Gnomad4 SAS AF: 0.0143

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00204 Hom.: 1

Bravo AF: 0.00530

Asia WGS AF: 0.0250 AC: 89 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.000533

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 17, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 23, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Focal segmental glomerulosclerosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 27, 2021

- -

Finnish congenital nephrotic syndrome Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Congenital nephrotic syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
Cadd	Benign	5.6
Dann	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.27		Position offset: 10

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

Publications

LitVar

Other links and lift over

dbSNP: rs2073901; hg19: chr19-36334485; COSMIC: COSV62286562; COSMIC: COSV62286562;