rs33950747

Positions:

chr19-35848345-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 3P and 16B. PM1PP3BP6_Very_StrongBA1

The NM_004646.4(NPHS1):c.1223G>A(p.Arg408Gln) variant causes a missense change. The variant allele was found at a frequency of 0.061 in 1,614,022 control chromosomes in the GnomAD database, including 3,446 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R408R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.043 ( 192 hom., cov: 32)

Exomes 𝑓: 0.063 ( 3254 hom. )

Consequence

NPHS1
NM_004646.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 4.07

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in NM_004646.4

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 19-35848345-C-T is Benign according to our data. Variant chr19-35848345-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 259482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-35848345-C-T is described in Lovd as [Likely_pathogenic]. Variant chr19-35848345-C-T is described in Lovd as [Benign]. Variant chr19-35848345-C-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0621 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHS1	NM_004646.4 linkuse as main transcript	c.1223G>A	p.Arg408Gln	missense_variant	10/29	ENST00000378910.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHS1	ENST00000378910.10 linkuse as main transcript	c.1223G>A	p.Arg408Gln	missense_variant	10/29	1	NM_004646.4	P2	O60500-1
NPHS1	ENST00000353632.6 linkuse as main transcript	c.1223G>A	p.Arg408Gln	missense_variant	10/28	5		A2	O60500-2
NPHS1	ENST00000592132.1 linkuse as main transcript	n.230G>A		non_coding_transcript_exon_variant	3/4	3

Frequencies

GnomAD3 genomes

AF:

0.0434

AC:

6601

AN:

152084

Hom.:

192

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0108

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.0379

Gnomad ASJ

AF:

0.0254

Gnomad EAS

AF:

0.00115

Gnomad SAS

AF:

0.0234

Gnomad FIN

AF:

0.0887

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0637

Gnomad OTH

AF:

0.0334

GnomAD3 exomes

AF:

0.0487

AC:

12251

AN:

251370

Hom.:

389

AF XY:

0.0483

AC XY:

6565

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.0105

Gnomad AMR exome

AF:

0.0469

Gnomad ASJ exome

AF:

0.0272

Gnomad EAS exome

AF:

0.000489

Gnomad SAS exome

AF:

0.0254

Gnomad FIN exome

AF:

0.0897

Gnomad NFE exome

AF:

0.0630

Gnomad OTH exome

AF:

0.0483

GnomAD4 exome

AF:

0.0628

AC:

91858

AN:

1461820

Hom.:

3254

Cov.:

AF XY:

0.0614

AC XY:

44639

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.00944

Gnomad4 AMR exome

AF:

0.0453

Gnomad4 ASJ exome

AF:

0.0249

Gnomad4 EAS exome

AF:

0.000705

Gnomad4 SAS exome

AF:

0.0268

Gnomad4 FIN exome

AF:

0.0873

Gnomad4 NFE exome

AF:

0.0707

Gnomad4 OTH exome

AF:

0.0521

GnomAD4 genome

AF:

0.0434

AC:

6599

AN:

152202

Hom.:

192

Cov.:

AF XY:

0.0431

AC XY:

3206

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.0108

Gnomad4 AMR

AF:

0.0380

Gnomad4 ASJ

AF:

0.0254

Gnomad4 EAS

AF:

0.00116

Gnomad4 SAS

AF:

0.0236

Gnomad4 FIN

AF:

0.0887

Gnomad4 NFE

AF:

0.0636

Gnomad4 OTH

AF:

0.0331

Alfa

AF:

0.0562

Hom.:

446

Bravo

AF:

0.0399

TwinsUK

AF:

0.0680

AC:

252

ALSPAC

AF:

0.0719

AC:

277

ESP6500AA

AF:

0.0127

AC:

ESP6500EA

AF:

0.0634

AC:

545

ExAC

AF:

0.0473

AC:

5741

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.0584

EpiControl

AF:

0.0535

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Finnish congenital nephrotic syndrome

Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 20, 2015	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign - Stand Alone, for Nephrotic syndrome, type 1, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 15, 2019	This variant is associated with the following publications: (PMID: 31216994, 27884173, 9915943, 21228398, 20981092, 20507940, 11726550, 24742477) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 23, 2017	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Atypical hemolytic-uremic syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 09, 2021

- -

Congenital nephrotic syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.29

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.38

T;.

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.77

T;T

MetaRNN

Benign

0.0033

T;T

MetaSVM

Benign

-0.43

MutationAssessor

Uncertain

2.7

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.6

N;N

REVEL

Uncertain

0.47

Sift

Benign

0.15

T;T

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.29

MPC

0.75

ClinPred

0.028

GERP RS

5.5

Varity_R

0.26

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.52

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.52

Position offset: -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