chr19-35831699-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004646.4(NPHS1):c.3230A>G(p.Asn1077Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 1,602,890 control chromosomes in the GnomAD database, including 8,826 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 Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 881 hom., cov: 31)

Exomes 𝑓: 0.10 ( 7945 hom. )

Consequence

NPHS1
NM_004646.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.914

Publications

19 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=0.0020531416).

BP6

Variant 19-35831699-T-C is Benign according to our data. Variant chr19-35831699-T-C is described in ClinVar as Benign. ClinVar VariationId is 259496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004646.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHS1	NM_004646.4	MANE Select	c.3230A>G	p.Asn1077Ser	missense	Exon 24 of 29	NP_004637.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NPHS1	ENST00000378910.10	TSL:1 MANE Select	c.3230A>G	p.Asn1077Ser	missense	Exon 24 of 29	ENSP00000368190.4
NPHS1	ENST00000869106.1		c.3170A>G	p.Asn1057Ser	missense	Exon 24 of 29	ENSP00000539165.1
NPHS1	ENST00000869107.1		c.3035A>G	p.Asn1012Ser	missense	Exon 22 of 27	ENSP00000539166.1

Frequencies

GnomAD3 genomes

AF:

0.105

AC:

15946

AN:

151246

Hom.:

880

Cov.:

show subpopulations

Gnomad AFR

AF:

0.126

Gnomad AMI

AF:

0.133

Gnomad AMR

AF:

0.0951

Gnomad ASJ

AF:

0.155

Gnomad EAS

AF:

0.0103

Gnomad SAS

AF:

0.107

Gnomad FIN

AF:

0.117

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.0980

Gnomad OTH

AF:

0.0935

GnomAD2 exomes

AF:

0.0970

AC:

22452

AN:

231452

AF XY:

0.0977

show subpopulations

Gnomad AFR exome

AF:

0.123

Gnomad AMR exome

AF:

0.0865

Gnomad ASJ exome

AF:

0.153

Gnomad EAS exome

AF:

0.0102

Gnomad FIN exome

AF:

0.110

Gnomad NFE exome

AF:

0.0980

Gnomad OTH exome

AF:

0.104

GnomAD4 exome

AF:

0.101

AC:

146169

AN:

1451526

Hom.:

7945

Cov.:

AF XY:

0.101

AC XY:

72803

AN XY:

721406

show subpopulations

African (AFR)

AF:

0.136

AC:

4489

AN:

33122

American (AMR)

AF:

0.0854

AC:

3669

AN:

42940

Ashkenazi Jewish (ASJ)

AF:

0.155

AC:

4028

AN:

25914

East Asian (EAS)

AF:

0.00781

AC:

306

AN:

39170

South Asian (SAS)

AF:

0.113

AC:

9604

AN:

84898

European-Finnish (FIN)

AF:

0.108

AC:

5711

AN:

52656

Middle Eastern (MID)

AF:

0.125

AC:

690

AN:

5532

European-Non Finnish (NFE)

AF:

0.101

AC:

111681

AN:

1107322

Other (OTH)

AF:

0.0999

AC:

5991

AN:

59972

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

7554

15109

22663

30218

37772

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4152

8304

12456

16608

20760

<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:

0.106

AC:

15982

AN:

151364

Hom.:

881

Cov.:

AF XY:

0.106

AC XY:

7870

AN XY:

73920

show subpopulations

African (AFR)

AF:

0.126

AC:

5205

AN:

41236

American (AMR)

AF:

0.0953

AC:

1449

AN:

15200

Ashkenazi Jewish (ASJ)

AF:

0.155

AC:

538

AN:

3462

East Asian (EAS)

AF:

0.0103

AC:

AN:

5140

South Asian (SAS)

AF:

0.108

AC:

514

AN:

4756

European-Finnish (FIN)

AF:

0.117

AC:

1227

AN:

10476

Middle Eastern (MID)

AF:

0.119

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0980

AC:

6645

AN:

67794

Other (OTH)

AF:

0.0930

AC:

195

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

723

1445

2168

2890

3613

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

176

352

528

704

880

<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:

0.103

Hom.:

685

Bravo

AF:

0.103

TwinsUK

AF:

0.0998

AC:

370

ALSPAC

AF:

0.101

AC:

389

ESP6500AA

AF:

0.124

AC:

547

ESP6500EA

AF:

0.0966

AC:

831

ExAC

AF:

0.0929

AC:

11256

Asia WGS

AF:

0.0700

AC:

243

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Finnish congenital nephrotic syndrome (4)

not provided (4)

not specified (2)

Congenital nephrotic syndrome (1)

Focal segmental glomerulosclerosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Uncertain

0.58

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.79

MetaRNN

Benign

0.0021

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

PhyloP100

0.91

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-2.3

REVEL

Benign

0.11

Sift

Uncertain

0.018

Sift4G

Uncertain

0.026

Polyphen

0.010

Vest4

0.12

MPC

0.087

ClinPred

0.0042

GERP RS

1.7

Varity_R

0.068

gMVP

0.75

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over