rs145125791

Positions:

chr19-35850409-T-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS2

The NM_004646.4(NPHS1):c.563A>T(p.Asn188Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00799 in 1,614,106 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0060 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0082 ( 66 hom. )

Consequence

NPHS1
NM_004646.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:11

Conservation

PhyloP100: 0.514

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 -7 ACMG points.

PM1

In a disulfide_bond (size 57) in uniprot entity NPHN_HUMAN there are 8 pathogenic changes around while only 2 benign (80%) in NM_004646.4

BP4

Computational evidence support a benign effect (MetaRNN=0.025585592).

BP6

Variant 19-35850409-T-A is Benign according to our data. Variant chr19-35850409-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 282372.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Benign=3, Uncertain_significance=1}. Variant chr19-35850409-T-A is described in Lovd as [Benign]. Variant chr19-35850409-T-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHS1	NM_004646.4 linkuse as main transcript	c.563A>T	p.Asn188Ile	missense_variant	5/29	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.563A>T	p.Asn188Ile	missense_variant	5/29	1	NM_004646.4	ENSP00000368190	P2	O60500-1
NPHS1	ENST00000353632.6 linkuse as main transcript	c.563A>T	p.Asn188Ile	missense_variant	5/28	5		ENSP00000343634	A2	O60500-2

Frequencies

GnomAD3 genomes

AF:

0.00601

AC:

915

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00179

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00727

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00643

Gnomad FIN

AF:

0.00169

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00957

Gnomad OTH

AF:

0.00861

GnomAD3 exomes

AF:

0.00605

AC:

1521

AN:

251492

Hom.:

AF XY:

0.00636

AC XY:

864

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00141

Gnomad AMR exome

AF:

0.00428

Gnomad ASJ exome

AF:

0.00198

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00591

Gnomad FIN exome

AF:

0.00236

Gnomad NFE exome

AF:

0.00927

Gnomad OTH exome

AF:

0.00700

GnomAD4 exome

AF:

0.00820

AC:

11985

AN:

1461836

Hom.:

Cov.:

AF XY:

0.00806

AC XY:

5865

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00134

Gnomad4 AMR exome

AF:

0.00487

Gnomad4 ASJ exome

AF:

0.00222

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00539

Gnomad4 FIN exome

AF:

0.00311

Gnomad4 NFE exome

AF:

0.00945

Gnomad4 OTH exome

AF:

0.00782

GnomAD4 genome

AF:

0.00600

AC:

914

AN:

152270

Hom.:

Cov.:

AF XY:

0.00623

AC XY:

464

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00178

Gnomad4 AMR

AF:

0.00726

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00643

Gnomad4 FIN

AF:

0.00169

Gnomad4 NFE

AF:

0.00956

Gnomad4 OTH

AF:

0.00852

Alfa

AF:

0.00837

Hom.:

Bravo

AF:

0.00631

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.0101

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00977

AC:

ExAC

AF:

0.00619

AC:

751

Asia WGS

AF:

0.00404

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Finnish congenital nephrotic syndrome

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Feb 22, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 15, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 30, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 30, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 11, 2021	Variant summary: NPHS1 c.563A>T (p.Asn188Ile) results in a non-conservative amino acid change located in the CD80-like, immunoglobulin C2-set domain (IPR013162) 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 0.006 in 251492 control chromosomes, predominantly at a frequency of 0.0093 within the Non-Finnish European subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2.8 fold of 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 a benign polymorphism found primarily in populations of Non-Finnish European origin. c.563A>T has been reported in the literature in individuals affected with a variety of renal phenotypes such as congenital FSGS (example Koziell_2002), Alport syndrome (example, Gibson_2013, Chatterjee_2013) and in settings of multigene panel testing for pediatric Nephrotic syndrome (example Abid_2018). In families with this variant, a clear lack of segregation of this variant with the underlying clinical phenotype of Alport syndrome attributed to a causative variant in the COL4A5 gene was noted (example, Gibson_2013, Chatterjee_2013). Multiple reports of co-occurrences with other pathogenic variant(s) have been reported (homozygous NPHS2 (436)delA, in two siblings with FSGS, Koziell_2002; COL4A5 c.973G>A, p.Gly325Arg, Gibson_2013; COL4A5 c.3482G>A, p.Gly1161Glu, Chatterjee_2013), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 citing a predominant classification of likely benign (n=4)/benign (n=2), VUS (n=1). Based on the evidence outlined above, the variant was classified as benign. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	NPHS1: BP4, BS2 -
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

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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

NPHS1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 11, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Focal segmental glomerulosclerosis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 17, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.30

T;.

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.79

T;T

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.026

T;T

MetaSVM

Benign

-0.79

MutationAssessor

Benign

1.7

L;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.25

Sift

Benign

0.56

T;T

Sift4G

Uncertain

0.0020

D;D

Polyphen

0.57

P;.

Vest4

0.79

MVP

0.83

MPC

0.44

ClinPred

0.0048

GERP RS

2.2

Varity_R

0.22

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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