NM_001330239.4:c.4040A>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.4040A>C(p.Asp1347Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0572 in 1,614,036 control chromosomes in the GnomAD database, including 2,953 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.044 ( 167 hom., cov: 33)

Exomes 𝑓: 0.059 ( 2786 hom. )

Consequence

TJP1
NM_001330239.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 7.67

Publications

21 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=0.0036012828).

BP6

Variant 15-29716773-T-G is Benign according to our data. Variant chr15-29716773-T-G is described in ClinVar as Benign. ClinVar VariationId is 3056593.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0709 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330239.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TJP1	NM_001330239.4	MANE Select	c.4040A>C	p.Asp1347Ala	missense	Exon 23 of 28	NP_001317168.1
TJP1	NM_001301025.3		c.4319A>C	p.Asp1440Ala	missense	Exon 24 of 29	NP_001287954.2
TJP1	NM_001355012.2		c.4319A>C	p.Asp1440Ala	missense	Exon 24 of 29	NP_001341941.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TJP1	ENST00000614355.5	TSL:5 MANE Select	c.4040A>C	p.Asp1347Ala	missense	Exon 23 of 28	ENSP00000483470.2
TJP1	ENST00000346128.10	TSL:1	c.4040A>C	p.Asp1347Ala	missense	Exon 23 of 28	ENSP00000281537.7
TJP1	ENST00000400011.6	TSL:1	c.3812A>C	p.Asp1271Ala	missense	Exon 23 of 28	ENSP00000382890.2

Frequencies

GnomAD3 genomes

AF:

0.0444

AC:

6754

AN:

152154

Hom.:

167

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0238

Gnomad AMI

AF:

0.0450

Gnomad AMR

AF:

0.0218

Gnomad ASJ

AF:

0.0544

Gnomad EAS

AF:

0.0329

Gnomad SAS

AF:

0.0777

Gnomad FIN

AF:

0.0528

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0587

Gnomad OTH

AF:

0.0430

GnomAD2 exomes

AF:

0.0494

AC:

12333

AN:

249524

AF XY:

0.0528

show subpopulations

Gnomad AFR exome

AF:

0.0229

Gnomad AMR exome

AF:

0.0190

Gnomad ASJ exome

AF:

0.0518

Gnomad EAS exome

AF:

0.0343

Gnomad FIN exome

AF:

0.0499

Gnomad NFE exome

AF:

0.0545

Gnomad OTH exome

AF:

0.0492

GnomAD4 exome

AF:

0.0585

AC:

85583

AN:

1461764

Hom.:

2786

Cov.:

AF XY:

0.0595

AC XY:

43282

AN XY:

727158

show subpopulations

African (AFR)

AF:

0.0225

AC:

753

AN:

33478

American (AMR)

AF:

0.0205

AC:

917

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0554

AC:

1447

AN:

26136

East Asian (EAS)

AF:

0.0277

AC:

1101

AN:

39692

South Asian (SAS)

AF:

0.0835

AC:

7201

AN:

86248

European-Finnish (FIN)

AF:

0.0505

AC:

2696

AN:

53412

Middle Eastern (MID)

AF:

0.0459

AC:

265

AN:

5768

European-Non Finnish (NFE)

AF:

0.0609

AC:

67715

AN:

1111918

Other (OTH)

AF:

0.0578

AC:

3488

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

4399

8798

13196

17595

21994

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2592

5184

7776

10368

12960

<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:

0.0444

AC:

6756

AN:

152272

Hom.:

167

Cov.:

AF XY:

0.0437

AC XY:

3253

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.0239

AC:

994

AN:

41562

American (AMR)

AF:

0.0218

AC:

333

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0544

AC:

189

AN:

3472

East Asian (EAS)

AF:

0.0328

AC:

170

AN:

5190

South Asian (SAS)

AF:

0.0774

AC:

373

AN:

4820

European-Finnish (FIN)

AF:

0.0528

AC:

560

AN:

10606

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0588

AC:

3996

AN:

68016

Other (OTH)

AF:

0.0425

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

338

676

1013

1351

1689

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

258

344

430

<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:

0.0524

Hom.:

1028

Bravo

AF:

0.0401

TwinsUK

AF:

0.0626

AC:

232

ALSPAC

AF:

0.0695

AC:

268

ESP6500AA

AF:

0.0273

AC:

102

ESP6500EA

AF:

0.0572

AC:

470

ExAC

AF:

0.0490

AC:

5921

Asia WGS

AF:

0.0550

AC:

195

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

TJP1-related disorder

Benign:1

Jul 13, 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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Benign

-0.085

BayesDel_noAF

Pathogenic

0.17

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.0036

MetaSVM

Benign

-0.57

MutationAssessor

Benign

1.8

PhyloP100

7.7

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.35

Sift

Pathogenic

0.0

Sift4G

Benign

0.088

Polyphen

1.0

Vest4

0.75

MPC

0.44

ClinPred

0.021

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.53

gMVP

0.49

Mutation Taster

=95/5

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over