rs386833912

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1PM5PP3_ModeratePP5_Very_Strong

The NM_004646.4(NPHS1):c.2417C>A(p.Ala806Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,614,028 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A806T) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

NPHS1
NM_004646.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 2.37

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

congenital nephrotic syndrome, Finnish type
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Myriad Women’s Health, G2P, Labcorp Genetics (formerly Invitae), ClinGen
familial idiopathic steroid-resistant nephrotic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

NPHS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 6 uncertain in NM_004646.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-35842469-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1477778.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.92

PP5

Variant 19-35842468-G-T is Pathogenic according to our data. Variant chr19-35842468-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 56473.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHS1	NM_004646.4 link	c.2417C>A	p.Ala806Asp	missense_variant	Exon 18 of 29	ENST00000378910.10	NP_004637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHS1	ENST00000378910.10 link	c.2417C>A	p.Ala806Asp	missense_variant	Exon 18 of 29	1	NM_004646.4	ENSP00000368190.4
NPHS1	ENST00000353632.6 link	c.2417C>A	p.Ala806Asp	missense_variant	Exon 18 of 28	5		ENSP00000343634.5

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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

GnomAD2 exomes

AF:

0.00000795

AC:

AN:

251454

AF XY:

0.00000736

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000198

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000252

AC:

AN:

1112000

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74330

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000241

AC:

AN:

41432

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Finnish congenital nephrotic syndrome

Pathogenic:9

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 15, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jun 12, 2014

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Sep 16, 2020

Vasylyeva lab, Texas Tech University Health Sciences Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 07, 2016

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 15, 2024

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: NPHS1 c.2417C>A (p.Ala806Asp) results in a non-conservative amino acid change located in the Immunoglobulin subtype 2 domain (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 8e-06 in 251454 control chromosomes. c.2417C>A has been reported in the literature in individuals affected with Nephrotic Syndrome, Type 1 (example: Lenkkeri_1999, Santin_2009, Lovric_2014). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect impairs cellular localization (Liu_2001). The following publications have been ascertained in the context of this evaluation (PMID: 9915943, 19812541, 11726550, 24742477). ClinVar contains an entry for this variant (Variation ID: 56473). Based on the evidence outlined above, the variant was classified as pathogenic. -

Jun 01, 2022

Solve-RD Consortium

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:provider interpretation

Variant confirmed as disease-causing by referring clinical team -

Aug 22, 2018

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The NPHS1 c.2417C>A (p.Ala806Asp) variant has been reported in at least five studies and is found in a homozygous state in three probands and in a compound heterozygous state in two probands with congenital Finnish nephrosis (Lenkerri et al. 1999; Santin et al. 2009; Santin et al. 2011; Lovric et al. 2014; Machuca et al. 2014; Berody et al. 2018). The p.Ala806Asp variant was absent from 30 controls and is reported at a frequency of 0.00002 in the European (non-Finnish) population of the Exome Aggregation Consortium but this is based on one allele so the variant is presumed to be rare. Immunostaining of cells with wildtype NPHS1 demonstrated expression at the plasma membrane, whereas in cells containing the p.Ala806Asp variant there was no detectable surface staining observed (Liu et al. 2001). Based on the evidence, the p.Ala806Asp variant is classified as pathogenic for congenital nephrotic syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided

Pathogenic:3

Jun 19, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate that this variant impairs transport of mutated proteins to the cell surface (PMID: 11726550); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24742477, 21415313, 32462257, 19812541, 20507940, 9915943, 11317351, 23349334, 11726550, 29474669, 33980730) -

Dec 30, 2019

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The frequency of this variant in the general population is consistent with pathogenicity. Conflicting predictions of the effect on the protein. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function. -

Mar 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 806 of the NPHS1 protein (p.Ala806Asp). This variant is present in population databases (rs386833912, gnomAD 0.002%). This missense change has been observed in individuals with congenital nephrotic syndrome (PMID: 9915943, 20507940, 21415313, 24742477, 33980730). ClinVar contains an entry for this variant (Variation ID: 56473). 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) performed at Invitae indicates that this missense variant is expected to disrupt NPHS1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects NPHS1 function (PMID: 11726550). This variant disrupts the p.Ala806 amino acid residue in NPHS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23349334; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.54

D;.

Eigen

Uncertain

0.37

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.77

T;T

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.92

D;D

MetaSVM

Benign

-1.0

MutationAssessor

Pathogenic

3.2

M;M

PhyloP100

2.4

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-4.1

D;D

REVEL

Uncertain

0.35

Sift

Uncertain

0.0030

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.53

MutPred

0.77

Gain of catalytic residue at A806 (P = 0.0388);Gain of catalytic residue at A806 (P = 0.0388);

MVP

0.93

MPC

0.64

ClinPred

0.90

GERP RS

4.5

Varity_R

0.74

gMVP

0.88

Mutation Taster

=20/80

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over