rs140808195

Positions:

• chr19-35848629-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_004646.4(NPHS1):​c.1170+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00643 in 1,613,042 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0038 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0067 (42 hom.)
• Consequence: NPHS1 NM_004646.4 splice_region, intron
• Scores: Splicing: ADA: 0.00006057
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -0.635

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 19-35848629-C-T is Benign according to our data. Variant chr19-35848629-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 259480.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=2}. Variant chr19-35848629-C-T is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAdExome4 at 42 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHS1	NM_004646.4	c.1170+8G>A		splice_region_variant, intron_variant		ENST00000378910.10	NP_004637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHS1	ENST00000378910.10	c.1170+8G>A		splice_region_variant, intron_variant		1	NM_004646.4	ENSP00000368190.4
NPHS1	ENST00000353632.6	c.1170+8G>A		splice_region_variant, intron_variant		5		ENSP00000343634.5
NPHS1	ENST00000592132.1	n.177+8G>A		splice_region_variant, intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.00381 AC: 580 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00669

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.00392 AC: 982 AN: 250218 Hom.: 5 AF XY: 0.00384 AC XY: 520 AN XY: 135494

Gnomad AFR exome AF: 0.00149

Gnomad AMR exome AF: 0.000955

Gnomad ASJ exome AF: 0.00299

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00111

Gnomad FIN exome AF: 0.000979

Gnomad NFE exome AF: 0.00725

Gnomad OTH exome AF: 0.00344

GnomAD4 exome AF: 0.00670 AC: 9785 AN: 1460794 Hom.: 42 Cov.: 32 AF XY: 0.00642 AC XY: 4662 AN XY: 726706

Gnomad4 AFR exome AF: 0.00138

Gnomad4 AMR exome AF: 0.000716

Gnomad4 ASJ exome AF: 0.00257

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000917

Gnomad4 FIN exome AF: 0.00126

Gnomad4 NFE exome AF: 0.00834

Gnomad4 OTH exome AF: 0.00362

GnomAD4 genome AF: 0.00381 AC: 580 AN: 152248 Hom.: 0 Cov.: 32 AF XY: 0.00386 AC XY: 287 AN XY: 74434

Gnomad4 AFR AF: 0.00147

Gnomad4 AMR AF: 0.00261

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00669

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.00602 Hom.: 3

Bravo AF: 0.00386

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00627

EpiControl AF: 0.00533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	NPHS1: BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 23, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Congenital nephrotic syndrome Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Focal segmental glomerulosclerosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 27, 2021

- -

Finnish congenital nephrotic syndrome Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 10, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	12
DANN	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000061
dbscSNV1_RF	Benign	0.028
SpliceAI score (max)		0.43		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.43		Position offset: 3

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

Publications

LitVar

Other links and lift over

dbSNP: rs140808195; hg19: chr19-36339531;