19-35849285-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM1BP6_Very_StrongBS1BS2

The NM_004646.4(NPHS1):c.791C>G(p.Pro264Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0149 in 1,613,038 control chromosomes in the GnomAD database, including 229 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P264Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.018 ( 34 hom., cov: 32)

Exomes 𝑓: 0.015 ( 195 hom. )

Consequence

NPHS1
NM_004646.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.0530

Publications

12 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: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
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.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 5 uncertain in NM_004646.4

BP6

Variant 19-35849285-G-C is Benign according to our data. Variant chr19-35849285-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 198518.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 = 0.0179 (2724/152250) while in subpopulation AFR AF = 0.0218 (908/41568). AF 95% confidence interval is 0.0207. There are 34 homozygotes in GnomAd4. There are 1382 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 34 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHS1	NM_004646.4	MANE Select	c.791C>G	p.Pro264Arg	missense	Exon 7 of 29	NP_004637.1	O60500-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NPHS1	ENST00000378910.10	TSL:1 MANE Select	c.791C>G	p.Pro264Arg	missense	Exon 7 of 29	ENSP00000368190.4	O60500-1
NPHS1	ENST00000869106.1		c.791C>G	p.Pro264Arg	missense	Exon 7 of 29	ENSP00000539165.1
NPHS1	ENST00000353632.6	TSL:5	c.791C>G	p.Pro264Arg	missense	Exon 7 of 28	ENSP00000343634.5	O60500-2

Frequencies

GnomAD3 genomes

AF:

0.0179

AC:

2726

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0219

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.0109

Gnomad ASJ

AF:

0.0216

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00703

Gnomad FIN

AF:

0.0362

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0162

Gnomad OTH

AF:

0.0158

GnomAD2 exomes

AF:

0.0148

AC:

3682

AN:

249158

AF XY:

0.0147

show subpopulations

Gnomad AFR exome

AF:

0.0216

Gnomad AMR exome

AF:

0.00927

Gnomad ASJ exome

AF:

0.0216

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0321

Gnomad NFE exome

AF:

0.0154

Gnomad OTH exome

AF:

0.0176

GnomAD4 exome

AF:

0.0146

AC:

21307

AN:

1460788

Hom.:

195

Cov.:

AF XY:

0.0146

AC XY:

10606

AN XY:

726704

show subpopulations

African (AFR)

AF:

0.0207

AC:

692

AN:

33460

American (AMR)

AF:

0.0104

AC:

463

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0205

AC:

537

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39690

South Asian (SAS)

AF:

0.00969

AC:

835

AN:

86204

European-Finnish (FIN)

AF:

0.0285

AC:

1508

AN:

52896

Middle Eastern (MID)

AF:

0.0287

AC:

154

AN:

5374

European-Non Finnish (NFE)

AF:

0.0144

AC:

16046

AN:

1111978

Other (OTH)

AF:

0.0178

AC:

1071

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

1203

2405

3608

4810

6013

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

594

1188

1782

2376

2970

<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:

0.0179

AC:

2724

AN:

152250

Hom.:

Cov.:

AF XY:

0.0186

AC XY:

1382

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.0218

AC:

908

AN:

41568

American (AMR)

AF:

0.0108

AC:

165

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0216

AC:

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5166

South Asian (SAS)

AF:

0.00683

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0362

AC:

384

AN:

10600

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0162

AC:

1104

AN:

67998

Other (OTH)

AF:

0.0156

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

142

284

427

569

711

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.00555

Hom.:

Bravo

AF:

0.0163

TwinsUK

AF:

0.0151

AC:

ALSPAC

AF:

0.0132

AC:

ESP6500AA

AF:

0.0166

AC:

ESP6500EA

AF:

0.0157

AC:

135

ExAC

AF:

0.0141

AC:

1711

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.0192

EpiControl

AF:

0.0188

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

not specified (3)

Finnish congenital nephrotic syndrome (2)

Congenital nephrotic syndrome (1)

Focal segmental glomerulosclerosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.30

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.072

LIST_S2

Benign

0.73

MetaRNN

Benign

0.022

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.48

PhyloP100

-0.053

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.86

REVEL

Benign

0.16

Sift

Benign

0.17

Sift4G

Uncertain

0.027

Polyphen

0.68

Vest4

0.29

MPC

0.31

ClinPred

0.0084

GERP RS

1.6

Varity_R

0.10

gMVP

0.64

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.32

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.32

Position offset: 0

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