rs528950

Positions:

chr19-35845356-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004646.4(NPHS1):c.1930+12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00198 in 1,614,148 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 33 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 30 hom. )

Consequence

NPHS1
NM_004646.4 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.450

Variant links:

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 links:

NPHS1 (HGNC:):

NPHS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 19-35845356-C-T is Benign according to our data. Variant chr19-35845356-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 259486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0106 (1619/152344) while in subpopulation AFR AF= 0.0373 (1550/41580). AF 95% confidence interval is 0.0357. There are 33 homozygotes in gnomad4. There are 755 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHS1	NM_004646.4 linkuse as main transcript	c.1930+12G>A		intron_variant		ENST00000378910.10	NP_004637.1	O60500-1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
NPHS1	ENST00000378910.10 linkuse as main transcript	c.1930+12G>A	intron_variant	1	NM_004646.4	ENSP00000368190.4	O60500-1
NPHS1	ENST00000585400.1 linkuse as main transcript	n.112+43G>A	intron_variant	1
NPHS1	ENST00000353632.6 linkuse as main transcript	c.1930+12G>A	intron_variant	5		ENSP00000343634.5	O60500-2

Frequencies

GnomAD3 genomes

AF:

0.0106

AC:

1619

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0374

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00340

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00621

GnomAD3 exomes

AF:

0.00266

AC:

667

AN:

251124

Hom.:

AF XY:

0.00191

AC XY:

260

AN XY:

135846

show subpopulations

Gnomad AFR exome

AF:

0.0376

Gnomad AMR exome

AF:

0.00133

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000705

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.00108

AC:

1583

AN:

1461804

Hom.:

Cov.:

AF XY:

0.000945

AC XY:

687

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.0387

Gnomad4 AMR exome

AF:

0.00172

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000863

Gnomad4 OTH exome

AF:

0.00179

GnomAD4 genome

AF:

0.0106

AC:

1619

AN:

152344

Hom.:

Cov.:

AF XY:

0.0101

AC XY:

755

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.0373

Gnomad4 AMR

AF:

0.00340

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00615

Alfa

AF:

0.00742

Hom.:

Bravo

AF:

0.0122

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2021	See Variant Classification Assertion Criteria. -

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.

Dec 05, 2019

- -

Congenital nephrotic syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

DANN

Benign

0.90

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over