chr19-35846016-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3BP6

The NM_004646.4(NPHS1):c.1619C>A(p.Ala540Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000953 in 1,422,266 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A540A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 1 hom. )

Consequence

NPHS1
NM_004646.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: -0.101

Publications

1 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: Uncertain_significance. The variant received 0 ACMG points.

PP3

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

BP6

Variant 19-35846016-G-T is Benign according to our data. Variant chr19-35846016-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 447874.

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.1619C>A	p.Ala540Glu	missense	Exon 12 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.1619C>A	p.Ala540Glu	missense	Exon 12 of 29	ENSP00000368190.4	O60500-1
NPHS1	ENST00000869106.1		c.1559C>A	p.Ala520Glu	missense	Exon 12 of 29	ENSP00000539165.1
NPHS1	ENST00000353632.6	TSL:5	c.1619C>A	p.Ala540Glu	missense	Exon 12 of 28	ENSP00000343634.5	O60500-2

Frequencies

GnomAD3 genomes

AF:

0.000492

AC:

AN:

146490

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000348

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000869

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000323

AC:

AN:

194768

AF XY:

0.000295

show subpopulations

Gnomad AFR exome

AF:

0.000616

Gnomad AMR exome

AF:

0.0000346

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000638

Gnomad OTH exome

AF:

0.000392

GnomAD4 exome

AF:

0.00101

AC:

1283

AN:

1275776

Hom.:

Cov.:

AF XY:

0.000895

AC XY:

565

AN XY:

631044

show subpopulations

African (AFR)

AF:

0.000358

AC:

AN:

27944

American (AMR)

AF:

0.0000284

AC:

AN:

35156

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19504

East Asian (EAS)

AF:

0.00

AC:

AN:

25342

South Asian (SAS)

AF:

0.00

AC:

AN:

80164

European-Finnish (FIN)

AF:

0.0000278

AC:

AN:

36016

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4892

European-Non Finnish (NFE)

AF:

0.00125

AC:

1249

AN:

997990

Other (OTH)

AF:

0.000451

AC:

AN:

48768

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

136

203

271

339

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

186

248

310

<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:

0.000492

AC:

AN:

146490

Hom.:

Cov.:

AF XY:

0.000448

AC XY:

AN XY:

71472

show subpopulations

African (AFR)

AF:

0.000348

AC:

AN:

40284

American (AMR)

AF:

0.00

AC:

AN:

14742

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3432

East Asian (EAS)

AF:

0.00

AC:

AN:

4338

South Asian (SAS)

AF:

0.00

AC:

AN:

4036

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9682

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.000869

AC:

AN:

66732

Other (OTH)

AF:

0.00

AC:

AN:

2052

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000915

Hom.:

Bravo

AF:

0.000434

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000815

AC:

ExAC

AF:

0.000141

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Finnish congenital nephrotic syndrome (2)

not provided (2)

Congenital nephrotic syndrome (1)

NPHS1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.20

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.57

M_CAP

Benign

0.085

MetaRNN

Benign

0.030

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.0

PhyloP100

-0.10

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.62

REVEL

Benign

0.15

Sift

Benign

0.88

Sift4G

Benign

0.37

Polyphen

0.079

Vest4

0.19

MVP

0.52

MPC

0.20

ClinPred

0.0067

GERP RS

-0.16

Varity_R

0.081

gMVP

0.61

Mutation Taster

=83/17

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.75

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.75

Position offset: -1

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