chr19-35849285-G-C

Position:

chr19-35849285-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The ENST00000378910.10(NPHS1):c.791C>G(p.Pro264Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0149 in 1,613,038 control chromosomes in the GnomAD database, including 229 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P264Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.018 ( 34 hom., cov: 32)

Exomes 𝑓: 0.015 ( 195 hom. )

Consequence

NPHS1
ENST00000378910.10 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0530

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 -16 ACMG points.

BP6

Variant 19-35849285-G-C is Benign according to our data. Variant chr19-35849285-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 198518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-35849285-G-C is described in Lovd as [Likely_pathogenic]. Variant chr19-35849285-G-C is described in Lovd as [Benign]. Variant chr19-35849285-G-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0179 (2724/152250) while in subpopulation AFR AF= 0.0218 (908/41568). AF 95% confidence interval is 0.0207. There are 34 homozygotes in gnomad4. There are 1382 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHS1	NM_004646.4 linkuse as main transcript	c.791C>G	p.Pro264Arg	missense_variant	7/29	ENST00000378910.10	NP_004637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHS1	ENST00000378910.10 linkuse as main transcript	c.791C>G	p.Pro264Arg	missense_variant	7/29	1	NM_004646.4	ENSP00000368190	P2	O60500-1
NPHS1	ENST00000353632.6 linkuse as main transcript	c.791C>G	p.Pro264Arg	missense_variant	7/28	5		ENSP00000343634	A2	O60500-2

Frequencies

GnomAD3 genomes

AF:

0.0179

AC:

2726

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0219

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.0109

Gnomad ASJ

AF:

0.0216

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00703

Gnomad FIN

AF:

0.0362

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0162

Gnomad OTH

AF:

0.0158

GnomAD3 exomes

AF:

0.0148

AC:

3682

AN:

249158

Hom.:

AF XY:

0.0147

AC XY:

1990

AN XY:

135120

show subpopulations

Gnomad AFR exome

AF:

0.0216

Gnomad AMR exome

AF:

0.00927

Gnomad ASJ exome

AF:

0.0216

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00892

Gnomad FIN exome

AF:

0.0321

Gnomad NFE exome

AF:

0.0154

Gnomad OTH exome

AF:

0.0176

GnomAD4 exome

AF:

0.0146

AC:

21307

AN:

1460788

Hom.:

195

Cov.:

AF XY:

0.0146

AC XY:

10606

AN XY:

726704

show subpopulations

Gnomad4 AFR exome

AF:

0.0207

Gnomad4 AMR exome

AF:

0.0104

Gnomad4 ASJ exome

AF:

0.0205

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00969

Gnomad4 FIN exome

AF:

0.0285

Gnomad4 NFE exome

AF:

0.0144

Gnomad4 OTH exome

AF:

0.0178

GnomAD4 genome

AF:

0.0179

AC:

2724

AN:

152250

Hom.:

Cov.:

AF XY:

0.0186

AC XY:

1382

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.0218

Gnomad4 AMR

AF:

0.0108

Gnomad4 ASJ

AF:

0.0216

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00683

Gnomad4 FIN

AF:

0.0362

Gnomad4 NFE

AF:

0.0162

Gnomad4 OTH

AF:

0.0156

Alfa

AF:

0.00811

Hom.:

Bravo

AF:

0.0163

TwinsUK

AF:

0.0151

AC:

ALSPAC

AF:

0.0132

AC:

ESP6500AA

AF:

0.0166

AC:

ESP6500EA

AF:

0.0157

AC:

135

ExAC

AF:

0.0141

AC:

1711

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.0192

EpiControl

AF:

0.0188

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	NPHS1: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 06, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 14, 2020	This variant is associated with the following publications: (PMID: 20507940, 24371179, 23595123, 20981092, 18443213, 21228398, 11854170, 27535533, 27884173, 26346198) -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 30, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 20, 2018	Variant summary: NPHS1 c.791C>G (p.Pro264Arg) results in a non-conservative amino acid change located in the Immunoglobulin-like domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.015 in 275302 control chromosomes in the gnomAD database, including 54 homozygotes. The observed variant frequency is approximately 4.5 fold above the estimated maximal expected allele frequency for a pathogenic variant in NPHS1 causing Nephrotic Syndrome, Type 1 phenotype (0.0034), strongly suggesting that the variant is benign. c.791C>G has been reported in the literature in individuals affected with Nephrotic Syndrome, Type 1, without strong evidence for causality. In addition, the variant was found in a patient in cis with a likely pathogenic NPHS1 mutation, which was inherited from a healthy father, further supporting a benign role (Fylaktou_2013). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Finnish congenital nephrotic syndrome

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The heterozygous p.Pro264Arg variant in NPHS1 has been identified in an individual with Finnish type congenital nephrotic syndrome (PMID: 11854170), but has also been identified in >3% of European (Finnish) chromosomes and 20 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive Finnish type congenital nephrotic syndrome. -

Focal segmental glomerulosclerosis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 09, 2022

- -

Congenital nephrotic syndrome

Benign:1

Likely 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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.74

DEOGEN2

Benign

0.30

T;.

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.072

LIST_S2

Benign

0.73

T;T

MetaRNN

Benign

0.022

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.48

N;N

MutationTaster

Benign

0.76

N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.86

N;N

REVEL

Benign

0.16

Sift

Benign

0.17

T;D

Sift4G

Uncertain

0.027

D;D

Polyphen

0.68

P;.

Vest4

0.29

MPC

0.31

ClinPred

0.0084

GERP RS

1.6

Varity_R

0.10

gMVP

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.32

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.32

Position offset: 0

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