chr15-29726423-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_001330239.4(TJP1):c.2368A>G(p.Ile790Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 1,613,616 control chromosomes in the GnomAD database, including 12,047 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.11 ( 970 hom., cov: 33)

Exomes 𝑓: 0.12 ( 11077 hom. )

Consequence

TJP1
NM_001330239.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 2.82

Publications

20 publications found

Variant links:

Genes affected

TJP1 (HGNC:11827): (tight junction protein 1) This gene encodes a member of the membrane-associated guanylate kinase (MAGUK) family of proteins, and acts as a tight junction adaptor protein that also regulates adherens junctions. Tight junctions regulate the movement of ions and macromolecules between endothelial and epithelial cells. The multidomain structure of this scaffold protein, including a postsynaptic density 95/disc-large/zona occludens (PDZ) domain, a Src homology (SH3) domain, a guanylate kinase (GuK) domain and unique (U) motifs all help to co-ordinate binding of transmembrane proteins, cytosolic proteins, and F-actin, which are required for tight junction function. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2017]

TJP1 Gene-Disease associations (from GenCC):

arrhythmogenic right ventricular cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

TJP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015475452).

BP6

Variant 15-29726423-T-C is Benign according to our data. Variant chr15-29726423-T-C is described in ClinVar as Benign. ClinVar VariationId is 3056098.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.213 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TJP1	NM_001330239.4 link	c.2368A>G	p.Ile790Val	missense_variant	Exon 18 of 28	ENST00000614355.5	NP_001317168.1	A0A087X0K9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TJP1	ENST00000614355.5 link	c.2368A>G	p.Ile790Val	missense_variant	Exon 18 of 28	5	NM_001330239.4	ENSP00000483470.2		A0A087X0K9

Frequencies

GnomAD3 genomes

AF:

0.107

AC:

16355

AN:

152150

Hom.:

970

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0715

Gnomad AMI

AF:

0.0625

Gnomad AMR

AF:

0.157

Gnomad ASJ

AF:

0.133

Gnomad EAS

AF:

0.126

Gnomad SAS

AF:

0.223

Gnomad FIN

AF:

0.0939

Gnomad MID

AF:

0.187

Gnomad NFE

AF:

0.109

Gnomad OTH

AF:

0.134

GnomAD2 exomes

AF:

0.133

AC:

33109

AN:

249330

AF XY:

0.137

show subpopulations

Gnomad AFR exome

AF:

0.0697

Gnomad AMR exome

AF:

0.167

Gnomad ASJ exome

AF:

0.134

Gnomad EAS exome

AF:

0.126

Gnomad FIN exome

AF:

0.0984

Gnomad NFE exome

AF:

0.111

Gnomad OTH exome

AF:

0.127

GnomAD4 exome

AF:

0.117

AC:

170403

AN:

1461348

Hom.:

11077

Cov.:

AF XY:

0.120

AC XY:

87360

AN XY:

726996

show subpopulations

African (AFR)

AF:

0.0709

AC:

2372

AN:

33472

American (AMR)

AF:

0.168

AC:

7493

AN:

44658

Ashkenazi Jewish (ASJ)

AF:

0.131

AC:

3423

AN:

26116

East Asian (EAS)

AF:

0.0876

AC:

3476

AN:

39682

South Asian (SAS)

AF:

0.234

AC:

20180

AN:

86196

European-Finnish (FIN)

AF:

0.0994

AC:

5310

AN:

53410

Middle Eastern (MID)

AF:

0.149

AC:

859

AN:

5768

European-Non Finnish (NFE)

AF:

0.108

AC:

119671

AN:

1111680

Other (OTH)

AF:

0.126

AC:

7619

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

7347

14693

22040

29386

36733

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4492

8984

13476

17968

22460

<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:

0.107

AC:

16351

AN:

152268

Hom.:

970

Cov.:

AF XY:

0.108

AC XY:

8065

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.0713

AC:

2963

AN:

41566

American (AMR)

AF:

0.157

AC:

2403

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.133

AC:

463

AN:

3472

East Asian (EAS)

AF:

0.126

AC:

653

AN:

5182

South Asian (SAS)

AF:

0.224

AC:

1081

AN:

4826

European-Finnish (FIN)

AF:

0.0939

AC:

995

AN:

10596

Middle Eastern (MID)

AF:

0.184

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.109

AC:

7396

AN:

68002

Other (OTH)

AF:

0.135

AC:

286

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

742

1484

2227

2969

3711

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

196

392

588

784

980

<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:

0.111

Hom.:

4369

Bravo

AF:

0.107

TwinsUK

AF:

0.106

AC:

394

ALSPAC

AF:

0.101

AC:

390

ESP6500AA

AF:

0.0700

AC:

259

ESP6500EA

AF:

0.110

AC:

902

ExAC

AF:

0.131

AC:

15842

Asia WGS

AF:

0.186

AC:

648

AN:

3478

EpiCase

AF:

0.117

EpiControl

AF:

0.116

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

TJP1-related disorder

Benign:1

Nov 20, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;T;.;T;.

Eigen

Benign

0.013

Eigen_PC

Benign

0.059

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.89

D;D;D;D;D

MetaRNN

Benign

0.0015

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

L;.;.;.;L

PhyloP100

2.8

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.80

N;N;N;.;N

REVEL

Benign

0.068

Sift

Benign

0.096

T;T;T;.;T

Sift4G

Uncertain

0.032

D;D;T;D;D

Polyphen

0.73

P;B;.;.;P

Vest4

0.17

MPC

0.90

ClinPred

0.029

GERP RS

3.5

Varity_R

0.14

gMVP

0.30

Mutation Taster

=99/1

polymorphism (auto)

(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

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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