chr19-35849310-G-A

Position:

chr19-35849310-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_004646.4(NPHS1):c.766C>T(p.Arg256Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000116 in 1,612,854 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000097 ( 1 hom. )

Consequence

NPHS1
NM_004646.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3B:1

Conservation

PhyloP100: 0.263

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.33311763).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHS1	NM_004646.4 linkuse as main transcript	c.766C>T	p.Arg256Trp	missense_variant	7/29	ENST00000378910.10	NP_004637.1	O60500-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHS1	ENST00000378910.10 linkuse as main transcript	c.766C>T	p.Arg256Trp	missense_variant	7/29	1	NM_004646.4	ENSP00000368190.4		O60500-1
NPHS1	ENST00000353632.6 linkuse as main transcript	c.766C>T	p.Arg256Trp	missense_variant	7/28	5		ENSP00000343634.5		O60500-2

Frequencies

GnomAD3 genomes

AF:

0.000296

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00373

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000233

AC:

AN:

249294

Hom.:

AF XY:

0.000266

AC XY:

AN XY:

135178

show subpopulations

Gnomad AFR exome

AF:

0.000875

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00137

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000972

AC:

142

AN:

1460572

Hom.:

Cov.:

AF XY:

0.000124

AC XY:

AN XY:

726616

show subpopulations

Gnomad4 AFR exome

AF:

0.000389

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00101

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000270

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000296

AC:

AN:

152282

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.000602

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00373

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Bravo

AF:

0.000196

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000189

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Finnish congenital nephrotic syndrome

Pathogenic:1Uncertain:1

Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 09, 2022	- -

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 08, 2022

Variant summary: NPHS1 c.766C>T (p.Arg256Trp) results in a non-conservative amino acid change located in the Immunoglobulin subtype domain (IPR003599) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 249294 control chromosomes, predominantly at a frequency of 0.0014 within the South Asian subpopulation in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in NPHS1 causing Nephrotic Syndrome, Type 1 (0.00023 vs 0.0034), allowing no conclusion about variant significance. c.766C>T has been reported in the literature as a non-informative genotype (second allele/zygosity not specified) and in at-least one instance as a presumed compound heterozygous genotype in cohorts of individuals with a variety of renal phenotypes such as congenital nephrotic syndrome (CNS), unspecified nephrotic syndrome (NS), steroid resistant nephrotic syndrome (SRNS) (example, Heeringa_2008, Machuca_2010, Abid_2012, Sadowski_2015). These data do not allow any conclusion about variant significance. 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 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.045

BayesDel_noAF

Uncertain

0.13

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

D;.

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.081

LIST_S2

Uncertain

0.88

D;D

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.33

T;T

MetaSVM

Uncertain

0.11

MutationAssessor

Uncertain

2.4

M;M

PrimateAI

Benign

0.43

PROVEAN

Pathogenic

-6.3

D;D

REVEL

Uncertain

0.57

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;.

Vest4

0.73

MVP

0.90

MPC

0.70

ClinPred

0.20

GERP RS

-4.2

Varity_R

0.47

gMVP

0.76

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