rs2285450

chr19-35851365-G-A

Variant summary

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

The NM_004646.4(NPHS1):c.294C>T(p.Ile98=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,613,202 control chromosomes in the GnomAD database, including 1,183 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (365 hom., cov: 32)
  • Exomes 𝑓: 0.0095 (818 hom.)
• Consequence: NPHS1 NM_004646.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.365

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]

KIRREL2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 19-35851365-G-A is Benign according to our data. Variant chr19-35851365-G-A is described in ClinVar as [Benign]. Clinvar id is 259492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-35851365-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.365 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHS1	NM_004646.4	c.294C>T	p.Ile98=	synonymous_variant	3/29	ENST00000378910.10
KIRREL2	XM_011527362.2			upstream_gene_variant
KIRREL2	XM_011527363.2			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHS1	ENST00000378910.10	c.294C>T	p.Ile98=	synonymous_variant	3/29	1	NM_004646.4	P2
NPHS1	ENST00000353632.6	c.294C>T	p.Ile98=	synonymous_variant	3/28	5		A2

Frequencies

GnomAD3 genomes AF: 0.0408 AC: 6201 AN: 152132 Hom.: 345 Cov.: 32

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0172

Gnomad ASJ AF: 0.0109

Gnomad EAS AF: 0.134

Gnomad SAS AF: 0.0186

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.0229

GnomAD3 exomes AF: 0.0217 AC: 5349 AN: 246642 Hom.: 318 AF XY: 0.0190 AC XY: 2544 AN XY: 133884

Gnomad AFR exome AF: 0.128

Gnomad AMR exome AF: 0.00680

Gnomad ASJ exome AF: 0.0136

Gnomad EAS exome AF: 0.133

Gnomad SAS exome AF: 0.0124

Gnomad FIN exome AF: 0.000284

Gnomad NFE exome AF: 0.000911

Gnomad OTH exome AF: 0.0122

GnomAD4 exome AF: 0.00949 AC: 13861 AN: 1460952 Hom.: 818 Cov.: 35 AF XY: 0.00911 AC XY: 6624 AN XY: 726750

Gnomad4 AFR exome AF: 0.133

Gnomad4 AMR exome AF: 0.00738

Gnomad4 ASJ exome AF: 0.0130

Gnomad4 EAS exome AF: 0.148

Gnomad4 SAS exome AF: 0.0130

Gnomad4 FIN exome AF: 0.000244

Gnomad4 NFE exome AF: 0.000486

Gnomad4 OTH exome AF: 0.0183

GnomAD4 genome AF: 0.0411 AC: 6250 AN: 152250 Hom.: 365 Cov.: 32 AF XY: 0.0409 AC XY: 3043 AN XY: 74456

Gnomad4 AFR AF: 0.122

Gnomad4 AMR AF: 0.0172

Gnomad4 ASJ AF: 0.0109

Gnomad4 EAS AF: 0.134

Gnomad4 SAS AF: 0.0180

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.000691

Gnomad4 OTH AF: 0.0222

Alfa AF: 0.0201 Hom.: 91

Bravo AF: 0.0472

Asia WGS AF: 0.0640 AC: 221 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 23, 2019	This variant is associated with the following publications: (PMID: 26147534) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Finnish congenital nephrotic syndrome Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 25, 2019

- -

Congenital nephrotic syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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	-0.47
Cadd	Benign	7.6
Dann	Benign	0.91

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

Publications

LitVar

Other links and lift over

dbSNP: rs2285450; hg19: chr19-36342267; COSMIC: COSV62288051; COSMIC: COSV62288051;