dbSNP rs17683205: TJP1:c.4373-88G>A (chr15-29709124-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001330239.4(TJP1):c.4373-88G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 1,310,008 control chromosomes in the GnomAD database, including 8,799 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.10 ( 869 hom., cov: 32)

Exomes 𝑓: 0.11 ( 7930 hom. )

Consequence

TJP1
NM_001330239.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.60

Publications

5 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.208 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TJP1	NM_001330239.4 link	c.4373-88G>A		intron_variant	Intron 24 of 27	ENST00000614355.5	NP_001317168.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TJP1	ENST00000614355.5 link	c.4373-88G>A		intron_variant	Intron 24 of 27	5	NM_001330239.4	ENSP00000483470.2

Frequencies

GnomAD3 genomes

AF:

0.102

AC:

15513

AN:

152002

Hom.:

868

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0674

Gnomad AMI

AF:

0.0625

Gnomad AMR

AF:

0.150

Gnomad ASJ

AF:

0.106

Gnomad EAS

AF:

0.126

Gnomad SAS

AF:

0.219

Gnomad FIN

AF:

0.0937

Gnomad MID

AF:

0.180

Gnomad NFE

AF:

0.103

Gnomad OTH

AF:

0.124

GnomAD4 exome

AF:

0.111

AC:

128059

AN:

1157888

Hom.:

7930

AF XY:

0.114

AC XY:

66165

AN XY:

578788

show subpopulations

African (AFR)

AF:

0.0661

AC:

1710

AN:

25870

American (AMR)

AF:

0.156

AC:

4772

AN:

30638

Ashkenazi Jewish (ASJ)

AF:

0.110

AC:

2138

AN:

19394

East Asian (EAS)

AF:

0.0861

AC:

3189

AN:

37020

South Asian (SAS)

AF:

0.230

AC:

15205

AN:

66118

European-Finnish (FIN)

AF:

0.0985

AC:

4486

AN:

45522

Middle Eastern (MID)

AF:

0.146

AC:

645

AN:

4432

European-Non Finnish (NFE)

AF:

0.102

AC:

90024

AN:

879420

Other (OTH)

AF:

0.119

AC:

5890

AN:

49474

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

5915

11831

17746

23662

29577

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3218

6436

9654

12872

16090

<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:

0.102

AC:

15509

AN:

152120

Hom.:

869

Cov.:

AF XY:

0.103

AC XY:

7688

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.0673

AC:

2793

AN:

41512

American (AMR)

AF:

0.150

AC:

2287

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.106

AC:

368

AN:

3470

East Asian (EAS)

AF:

0.126

AC:

648

AN:

5160

South Asian (SAS)

AF:

0.219

AC:

1056

AN:

4816

European-Finnish (FIN)

AF:

0.0937

AC:

992

AN:

10588

Middle Eastern (MID)

AF:

0.177

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.103

AC:

6992

AN:

67996

Other (OTH)

AF:

0.125

AC:

264

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

714

1428

2141

2855

3569

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

186

372

558

744

930

<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:

0.100

Hom.:

336

Bravo

AF:

0.102

Asia WGS

AF:

0.184

AC:

640

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.097

(source)

DANN

Benign

0.63

PhyloP100

-2.6

PromoterAI

0.0027

Neutral

(source)

Mutation Taster

=100/0

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

Computational scores

Splicing

Publications

Other links and lift over