19-35845551-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_004646.4(NPHS1):c.1758-11C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00883 in 1,611,298 control chromosomes in the GnomAD database, including 109 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 0.0077 ( 11 hom., cov: 32)

Exomes 𝑓: 0.0090 ( 98 hom. )

Consequence

NPHS1
NM_004646.4 intron

Scores

Splicing: ADA: 0.0007102

Clinical Significance

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

Conservation

PhyloP100: -0.0210

Publications

0 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 19-35845551-G-C is Benign according to our data. Variant chr19-35845551-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 328868.

BS2

High Homozygotes in GnomAd4 at 11 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHS1	NM_004646.4 link	c.1758-11C>G		intron_variant	Intron 13 of 28	ENST00000378910.10	NP_004637.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
NPHS1	ENST00000378910.10 link	c.1758-11C>G	intron_variant	Intron 13 of 28	1	NM_004646.4	ENSP00000368190.4
NPHS1	ENST00000353632.6 link	c.1758-11C>G	intron_variant	Intron 13 of 27	5		ENSP00000343634.5
NPHS1	ENST00000585400.1 link	n.-41C>G	upstream_gene_variant		1

Frequencies

GnomAD3 genomes

AF:

0.00769

AC:

1170

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00178

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.00281

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.0399

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00867

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00730

AC:

1740

AN:

238332

AF XY:

0.00704

show subpopulations

Gnomad AFR exome

AF:

0.00178

Gnomad AMR exome

AF:

0.00127

Gnomad ASJ exome

AF:

0.00205

Gnomad EAS exome

AF:

0.000113

Gnomad FIN exome

AF:

0.0363

Gnomad NFE exome

AF:

0.00833

Gnomad OTH exome

AF:

0.00395

GnomAD4 exome

AF:

0.00895

AC:

13062

AN:

1458986

Hom.:

Cov.:

AF XY:

0.00870

AC XY:

6312

AN XY:

725666

show subpopulations

African (AFR)

AF:

0.00111

AC:

AN:

33440

American (AMR)

AF:

0.00135

AC:

AN:

44372

Ashkenazi Jewish (ASJ)

AF:

0.00200

AC:

AN:

26020

East Asian (EAS)

AF:

0.0000757

AC:

AN:

39616

South Asian (SAS)

AF:

0.000407

AC:

AN:

85986

European-Finnish (FIN)

AF:

0.0356

AC:

1876

AN:

52756

Middle Eastern (MID)

AF:

0.000872

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.00952

AC:

10577

AN:

1110860

Other (OTH)

AF:

0.00693

AC:

417

AN:

60204

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

726

1452

2177

2903

3629

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

418

836

1254

1672

2090

<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:

0.00769

AC:

1171

AN:

152312

Hom.:

Cov.:

AF XY:

0.00894

AC XY:

666

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00180

AC:

AN:

41584

American (AMR)

AF:

0.00281

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00432

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.000622

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0399

AC:

424

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00867

AC:

590

AN:

68022

Other (OTH)

AF:

0.00379

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

118

176

235

294

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00682

Hom.:

Bravo

AF:

0.00474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

May 15, 2017

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The NPHS1 c.1758-11C>G variant involves the alteration of a non-conserved nucleotide in the intronic region . One in silico tool predicts a benign outcome for this variant. 3/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 649/102412 control chromosomes (1 homozygote), predominantly observed in the European (Finnish) subpopulation at a frequency of 0.035667 (160/4486). This frequency is about 9 times the estimated maximal expected allele frequency of a pathogenic NPHS1 variant in Finnish population (0.0039, see calculation in additional comments), suggesting this is likely a benign polymorphism found primarily in the populations of European (Finnish) origin. This variant has been reported in a patient with end stage renal disease who also carries a pathogenic WT1 variant (c.1385G>A/p.Arg462Gln). Although one other clinical diagnostic laboratory classified this variant as uncertain significance, multiple lines of evidence support neutrality of this variant. Therefore, this variant is classified as benign.

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NPHS1: BS2

Congenital nephrotic syndrome

Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

1.4

(source)

DANN

Benign

0.37

PhyloP100

-0.021

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00071

dbscSNV1_RF

Benign

0.12

SpliceAI score (max)

0.17

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