rs34320609

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004646.4(NPHS1):c.1175T>C(p.Leu392Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00814 in 1,614,128 control chromosomes in the GnomAD database, including 130 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 38 hom., cov: 32)

Exomes 𝑓: 0.0072 ( 92 hom. )

Consequence

NPHS1
NM_004646.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.986

Publications

13 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0051710904).

BP6

Variant 19-35848393-A-G is Benign according to our data. Variant chr19-35848393-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0167 (2543/152258) while in subpopulation AFR AF = 0.042 (1744/41544). AF 95% confidence interval is 0.0403. There are 38 homozygotes in GnomAd4. There are 1186 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 38 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHS1	NM_004646.4 link	c.1175T>C	p.Leu392Pro	missense_variant	Exon 10 of 29	ENST00000378910.10	NP_004637.1	O60500-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NPHS1	ENST00000378910.10 link	c.1175T>C	p.Leu392Pro	missense_variant	Exon 10 of 29	1	NM_004646.4	ENSP00000368190.4	O60500-1
NPHS1	ENST00000353632.6 link	c.1175T>C	p.Leu392Pro	missense_variant	Exon 10 of 28	5		ENSP00000343634.5	O60500-2
NPHS1	ENST00000592132.1 link	n.182T>C		non_coding_transcript_exon_variant	Exon 3 of 4	3

Frequencies

GnomAD3 genomes

AF:

0.0167

AC:

2539

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0420

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0153

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00332

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00716

Gnomad OTH

AF:

0.0182

GnomAD2 exomes

AF:

0.00829

AC:

2083

AN:

251344

AF XY:

0.00735

show subpopulations

Gnomad AFR exome

AF:

0.0433

Gnomad AMR exome

AF:

0.0125

Gnomad ASJ exome

AF:

0.00725

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000555

Gnomad NFE exome

AF:

0.00584

Gnomad OTH exome

AF:

0.0134

GnomAD4 exome

AF:

0.00724

AC:

10589

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00697

AC XY:

5072

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.0454

AC:

1521

AN:

33480

American (AMR)

AF:

0.0124

AC:

555

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00712

AC:

186

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00428

AC:

369

AN:

86256

European-Finnish (FIN)

AF:

0.000693

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.0111

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00654

AC:

7278

AN:

1112004

Other (OTH)

AF:

0.00959

AC:

579

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

621

1243

1864

2486

3107

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

294

588

882

1176

1470

<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:

0.0167

AC:

2543

AN:

152258

Hom.:

Cov.:

AF XY:

0.0159

AC XY:

1186

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0420

AC:

1744

AN:

41544

American (AMR)

AF:

0.0152

AC:

233

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00332

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.000565

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00716

AC:

487

AN:

68014

Other (OTH)

AF:

0.0180

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

133

266

400

533

666

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.00979

Hom.:

Bravo

AF:

0.0188

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.0427

AC:

188

ESP6500EA

AF:

0.00616

AC:

ExAC

AF:

0.00876

AC:

1064

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jul 21, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 09, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Oct 17, 2019

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: NPHS1 c.1175T>C (p.Leu392Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0083 in 251344 control chromosomes, predominantly at a frequency of 0.043 within the African or African-American subpopulation in the gnomAD database, including 20 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 12.82 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 African or African-American origin. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Focal segmental glomerulosclerosis

Benign:1

Jul 11, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital nephrotic syndrome

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

T;.

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.55

T;T

MetaRNN

Benign

0.0052

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

L;L

PhyloP100

0.99

PrimateAI

Uncertain

0.52

PROVEAN

Benign

1.8

N;N

REVEL

Benign

0.11

Sift

Benign

0.25

T;T

Sift4G

Uncertain

0.019

D;D

Polyphen

0.32

B;.

Vest4

0.38

MVP

0.56

MPC

0.28

ClinPred

0.0088

GERP RS

3.3

Varity_R

0.13

gMVP

0.72

Mutation Taster

=38/62

polymorphism (auto)

(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

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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