chr19-35851340-C-T

Position:

chr19-35851340-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3PP5

The ENST00000378910.10(NPHS1):c.319G>A(p.Ala107Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,613,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A107E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

NPHS1
ENST00000378910.10 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:3

Conservation

PhyloP100: 2.52

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 Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a disulfide_bond (size 58) in uniprot entity NPHN_HUMAN there are 10 pathogenic changes around while only 1 benign (91%) in ENST00000378910.10

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.798

PP5

Variant 19-35851340-C-T is Pathogenic according to our data. Variant chr19-35851340-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 56494.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=3}. Variant chr19-35851340-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHS1	NM_004646.4 linkuse as main transcript	c.319G>A	p.Ala107Thr	missense_variant	3/29	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.319G>A	p.Ala107Thr	missense_variant	3/29	1	NM_004646.4	ENSP00000368190	P2	O60500-1
NPHS1	ENST00000353632.6 linkuse as main transcript	c.319G>A	p.Ala107Thr	missense_variant	3/28	5		ENSP00000343634	A2	O60500-2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000161

AC:

AN:

249074

Hom.:

AF XY:

0.00000741

AC XY:

AN XY:

134936

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000267

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000322

AC:

AN:

1461464

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

727028

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000396

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000594

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Finnish congenital nephrotic syndrome

Pathogenic:3Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 03, 2018	The NPHS1 c.319G>A (p.Ala107Thr) variant has been reported in a compound heterozygous state with a splice site variant in one individual with congenital Finnish nephrosis (Philippe et al. 2008). The p.Ala107Thr variant was absent from 188 control chromosomes, but is reported at a frequency of 0.000027 in the European (non-Finnish) population from the Genome Aggregation Database. Functional studies in HeLa cells demonstrated that the p.Ala107Thr variant protein localized to the plasma membrane with wild type nephrin. In HEK293 cells, co-immunoprecipitation studies showed that both nephrin homodimerization and NEPH1 heterodimerization were intact and unaffected by the p.Ala107Thr variant (Philippe et al. 2008). Based on the limited evidence, the p.Ala107Thr variant is classified as a variant of unknown significance but suspicious for pathogenicity for congenital nephrotic syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 23, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 03, 2021	NM_004646.3(NPHS1):c.319G>A(A107T) is a missense variant classified as a variant of uncertain significance in the context of nephrotic syndrome, NPHS1-related. A107T has been observed in cases with relevant disease (PMID: 18614772, 20507940, 25349199). Functional assessments of this variant are available in the literature (PMID: 18614772). A107T has been observed in population frequency databases (gnomAD: OTH 0.02%). In summary, there is insufficient evidence to classify NM_004646.3(NPHS1):c.319G>A(A107T) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 27, 2023	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 107 of the NPHS1 protein (p.Ala107Thr). This variant is present in population databases (rs386833933, gnomAD 0.003%). This missense change has been observed in individual(s) with steroid-resistant nephrotic syndrome (PMID: 18614772, 25349199). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 56494). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NPHS1 protein function. Experimental studies have shown that this missense change does not substantially affect NPHS1 function (PMID: 18614772). This variant disrupts the p.Ala107 amino acid residue in NPHS1. Other variant(s) that disrupt this residue have been observed in individuals with NPHS1-related conditions (PMID: 20172850, 20798252), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 15, 2023

Variant summary: NPHS1 c.319G>A (p.Ala107Thr) results in a non-conservative amino acid change located in the Immunoglobulin subtype 2 (IPR003598) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 249074 control chromosomes (gnomAD). c.319G>A has been reported in the literature in individuals affected with Nephrotic Syndrome, Type 1, (Philippe_2008, Sadowski_2015), and one was reported as compound heterozygous with a (likely) pathogenic variant. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18614772, 25349199). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=2) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

T;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.71

T;T

M_CAP

Benign

0.081

MetaRNN

Pathogenic

0.80

D;D

MetaSVM

Benign

-0.37

MutationAssessor

Uncertain

2.6

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-2.7

D;D

REVEL

Uncertain

0.40

Sift

Benign

0.085

T;T

Sift4G

Uncertain

0.0070

D;D

Polyphen

0.99

D;.

Vest4

0.62

MVP

0.88

MPC

0.62

ClinPred

0.86

GERP RS

5.9

Varity_R

0.31

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