Genetic Variant TJP3:p.Arg766Trp (chr19-3746850-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001267560.2(TJP3):c.2296C>T(p.Arg766Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000572 in 1,551,654 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0030 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00032 ( 2 hom. )

Consequence

TJP3
NM_001267560.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.21

Variant links:

Genes affected

TJP3 (HGNC:11829): (tight junction protein 3) The protein encoded by this gene is a member of the membrane-associated guanylate kinase-like (MAGUK) protein family which is characterized by members having multiple PDZ domains, a single SH3 domain, and a single guanylate kinase-like (GUK)-domain. In addition, members of the zonula occludens protein subfamily have an acidic domain, a basic arginine-rich region, and a proline-rich domain. The protein encoded by this gene plays a role in the linkage between the actin cytoskeleton and tight-junctions and also sequesters cyclin D1 at tight junctions during mitosis. Alternative splicing results in multiple transcript variants encoding distinct isoforms. This gene has a partial pseudogene on chromosome 1. [provided by RefSeq, May 2012]

TJP3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010299504).

BP6

Variant 19-3746850-C-T is Benign according to our data. Variant chr19-3746850-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2649010.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TJP3	NM_001267560.2 link	c.2296C>T	p.Arg766Trp	missense_variant	Exon 18 of 21	ENST00000541714.7	NP_001254489.1	O95049-1
TJP3	NM_001267561.2 link	c.2323C>T	p.Arg775Trp	missense_variant	Exon 18 of 21		NP_001254490.1	O95049-4
TJP3	XM_047438611.1 link	c.2494C>T	p.Arg832Trp	missense_variant	Exon 18 of 21		XP_047294567.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TJP3	ENST00000541714.7 link	c.2296C>T	p.Arg766Trp	missense_variant	Exon 18 of 21	2	NM_001267560.2	ENSP00000439278.1		O95049-1

Frequencies

GnomAD3 genomes

AF:

0.00297

AC:

444

AN:

149744

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0101

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00146

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:

0.0000593

Gnomad OTH

AF:

0.00241

GnomAD3 exomes

AF:

0.000750

AC:

182

AN:

242666

Hom.:

AF XY:

0.000571

AC XY:

AN XY:

131376

show subpopulations

Gnomad AFR exome

AF:

0.00954

Gnomad AMR exome

AF:

0.000825

Gnomad ASJ exome

AF:

0.000102

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000274

Gnomad OTH exome

AF:

0.000676

GnomAD4 exome

AF:

0.000317

AC:

445

AN:

1401790

Hom.:

Cov.:

AF XY:

0.000274

AC XY:

191

AN XY:

697104

show subpopulations

Gnomad4 AFR exome

AF:

0.0107

Gnomad4 AMR exome

AF:

0.000870

Gnomad4 ASJ exome

AF:

0.0000421

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000353

Gnomad4 OTH exome

AF:

0.000516

GnomAD4 genome

AF:

0.00296

AC:

443

AN:

149864

Hom.:

Cov.:

AF XY:

0.00279

AC XY:

204

AN XY:

73234

show subpopulations

Gnomad4 AFR

AF:

0.0100

Gnomad4 AMR

AF:

0.00146

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000593

Gnomad4 OTH

AF:

0.00238

Alfa

AF:

0.00170

Hom.:

Bravo

AF:

0.00320

ESP6500AA

AF:

0.00954

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000965

AC:

117

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Sep 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TJP3: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

D;.;.;.

Eigen

Benign

0.045

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.33

LIST_S2

Uncertain

0.88

D;D;D;D

MetaRNN

Benign

0.010

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

M;.;.;.

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-3.5

D;D;.;.

REVEL

Benign

0.042

Sift

Uncertain

0.0060

D;D;.;.

Sift4G

Uncertain

0.0030

D;D;D;D

Polyphen

1.0

.;.;.;D

Vest4

0.31

MVP

0.46

MPC

0.25

ClinPred

0.037

GERP RS

1.2

Varity_R

0.26

gMVP

0.38

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over