19-35831368-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PP3_ModerateBP6_Very_StrongBA1

The NM_004646.4(NPHS1):c.3315G>A(p.Ser1105Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.379 in 1,613,270 control chromosomes in the GnomAD database, including 122,372 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1105S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.32 ( 9723 hom., cov: 30)

Exomes 𝑓: 0.39 ( 112649 hom. )

Consequence

NPHS1
NM_004646.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -2.20

Publications

24 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: Benign. The variant received -14 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 19-35831368-C-T is Benign according to our data. Variant chr19-35831368-C-T is described in ClinVar as Benign. ClinVar VariationId is 259497.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.644 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHS1	NM_004646.4 link	c.3315G>A	p.Ser1105Ser	synonymous_variant	Exon 26 of 29	ENST00000378910.10	NP_004637.1	O60500-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHS1	ENST00000378910.10 link	c.3315G>A	p.Ser1105Ser	synonymous_variant	Exon 26 of 29	1	NM_004646.4	ENSP00000368190.4		O60500-1
NPHS1	ENST00000353632.6 link	c.3195G>A	p.Ser1065Ser	synonymous_variant	Exon 25 of 28	5		ENSP00000343634.5		O60500-2

Frequencies

GnomAD3 genomes

AF:

0.324

AC:

49111

AN:

151728

Hom.:

9718

Cov.:

show subpopulations

Gnomad AFR

AF:

0.102

Gnomad AMI

AF:

0.446

Gnomad AMR

AF:

0.384

Gnomad ASJ

AF:

0.345

Gnomad EAS

AF:

0.663

Gnomad SAS

AF:

0.429

Gnomad FIN

AF:

0.488

Gnomad MID

AF:

0.247

Gnomad NFE

AF:

0.383

Gnomad OTH

AF:

0.351

GnomAD2 exomes

AF:

0.400

AC:

100518

AN:

251432

AF XY:

0.402

show subpopulations

Gnomad AFR exome

AF:

0.0995

Gnomad AMR exome

AF:

0.422

Gnomad ASJ exome

AF:

0.351

Gnomad EAS exome

AF:

0.648

Gnomad FIN exome

AF:

0.492

Gnomad NFE exome

AF:

0.381

Gnomad OTH exome

AF:

0.373

GnomAD4 exome

AF:

0.385

AC:

563048

AN:

1461424

Hom.:

112649

Cov.:

AF XY:

0.387

AC XY:

281213

AN XY:

727048

show subpopulations

African (AFR)

AF:

0.0880

AC:

2947

AN:

33474

American (AMR)

AF:

0.417

AC:

18632

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.349

AC:

9132

AN:

26134

East Asian (EAS)

AF:

0.655

AC:

25986

AN:

39698

South Asian (SAS)

AF:

0.405

AC:

34943

AN:

86252

European-Finnish (FIN)

AF:

0.483

AC:

25767

AN:

53402

Middle Eastern (MID)

AF:

0.275

AC:

1585

AN:

5766

European-Non Finnish (NFE)

AF:

0.379

AC:

421247

AN:

1111590

Other (OTH)

AF:

0.378

AC:

22809

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

21068

42136

63203

84271

105339

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13220

26440

39660

52880

66100

<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:

0.323

AC:

49121

AN:

151846

Hom.:

9723

Cov.:

AF XY:

0.332

AC XY:

24645

AN XY:

74164

show subpopulations

African (AFR)

AF:

0.102

AC:

4234

AN:

41448

American (AMR)

AF:

0.385

AC:

5867

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.345

AC:

1196

AN:

3466

East Asian (EAS)

AF:

0.662

AC:

3395

AN:

5126

South Asian (SAS)

AF:

0.428

AC:

2059

AN:

4812

European-Finnish (FIN)

AF:

0.488

AC:

5146

AN:

10538

Middle Eastern (MID)

AF:

0.248

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.383

AC:

25996

AN:

67908

Other (OTH)

AF:

0.357

AC:

749

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1539

3077

4616

6154

7693

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

494

988

1482

1976

2470

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.349

Hom.:

15485

Bravo

AF:

0.308

Asia WGS

AF:

0.546

AC:

1896

AN:

3478

EpiCase

AF:

0.370

EpiControl

AF:

0.366

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Jan 24, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 65% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 60. Only high quality variants are reported. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Finnish congenital nephrotic syndrome

Benign:3

Jun 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 28, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital nephrotic syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.42

PhyloP100

-2.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.90

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.90

Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over