chr19-35835720-T-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4BP6

The NM_004646.4(NPHS1):c.3151A>G(p.Thr1051Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 1,613,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1051R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 27)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

NPHS1
NM_004646.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.35

Publications

4 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.31731948).

BP6

Variant 19-35835720-T-C is Benign according to our data. Variant chr19-35835720-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 556220.

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.3151A>G	p.Thr1051Ala	missense	Exon 23 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.3151A>G	p.Thr1051Ala	missense	Exon 23 of 29	ENSP00000368190.4	O60500-1
NPHS1	ENST00000869106.1		c.3091A>G	p.Thr1031Ala	missense	Exon 23 of 29	ENSP00000539165.1
NPHS1	ENST00000353632.6	TSL:5	c.3151A>G	p.Thr1051Ala	missense	Exon 23 of 28	ENSP00000343634.5	O60500-2

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

151842

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

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:

0.000191

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.000167

AC:

AN:

251484

AF XY:

0.000162

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000193

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000127

AC:

185

AN:

1461598

Hom.:

Cov.:

AF XY:

0.000129

AC XY:

AN XY:

727104

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33462

American (AMR)

AF:

0.000403

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000124

AC:

138

AN:

1111800

Other (OTH)

AF:

0.000232

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000138

AC:

AN:

151960

Hom.:

Cov.:

AF XY:

0.000162

AC XY:

AN XY:

74242

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41484

American (AMR)

AF:

0.00

AC:

AN:

15226

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5082

South Asian (SAS)

AF:

0.00

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

67964

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

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:

0.000165

Hom.:

Bravo

AF:

0.000249

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000165

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000356

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Finnish congenital nephrotic syndrome (3)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.21

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.087

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.56

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.32

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.2

PhyloP100

1.4

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.51

REVEL

Uncertain

0.30

Sift

Benign

0.31

Sift4G

Benign

0.11

Polyphen

0.0080

Vest4

0.58

MVP

0.85

MPC

0.10

ClinPred

0.018

GERP RS

4.6

Varity_R

0.073

gMVP

0.33

Mutation Taster

=24/76

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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