dbSNP rs1046268: TJP3:p.Met898Thr (chr19-3750617-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001267560.2(TJP3):c.2693T>C(p.Met898Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.548 in 1,605,634 control chromosomes in the GnomAD database, including 243,832 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.51 ( 20484 hom., cov: 31)

Exomes 𝑓: 0.55 ( 223348 hom. )

Consequence

TJP3
NM_001267560.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.41

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:

APBA3 (HGNC:580): (amyloid beta precursor protein binding family A member 3) The protein encoded by this gene is a member of the X11 protein family. It is an adapter protein that interacts with the Alzheimer's disease amyloid precursor protein. This gene product is believed to be involved in signal transduction processes. This gene is a candidate gene for Alzheimer's disease. [provided by RefSeq, Jul 2008]

APBA3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.3942548E-6).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.635 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TJP3	NM_001267560.2 link	c.2693T>C	p.Met898Thr	missense_variant	Exon 21 of 21	ENST00000541714.7	NP_001254489.1	O95049-1
APBA3	NM_004886.4 link	c.*409A>G		downstream_gene_variant		ENST00000316757.4	NP_004877.1	O96018

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TJP3	ENST00000541714.7 link	c.2693T>C	p.Met898Thr	missense_variant	Exon 21 of 21	2	NM_001267560.2	ENSP00000439278.1		O95049-1
APBA3	ENST00000316757.4 link	c.*409A>G		downstream_gene_variant		1	NM_004886.4	ENSP00000315136.2		O96018

Frequencies

GnomAD3 genomes

AF:

0.508

AC:

76964

AN:

151580

Hom.:

20461

Cov.:

show subpopulations

Gnomad AFR

AF:

0.344

Gnomad AMI

AF:

0.394

Gnomad AMR

AF:

0.645

Gnomad ASJ

AF:

0.558

Gnomad EAS

AF:

0.654

Gnomad SAS

AF:

0.578

Gnomad FIN

AF:

0.582

Gnomad MID

AF:

0.500

Gnomad NFE

AF:

0.547

Gnomad OTH

AF:

0.546

GnomAD3 exomes

AF:

0.569

AC:

136125

AN:

239428

Hom.:

39446

AF XY:

0.566

AC XY:

73288

AN XY:

129530

show subpopulations

Gnomad AFR exome

AF:

0.338

Gnomad AMR exome

AF:

0.716

Gnomad ASJ exome

AF:

0.558

Gnomad EAS exome

AF:

0.652

Gnomad SAS exome

AF:

0.567

Gnomad FIN exome

AF:

0.565

Gnomad NFE exome

AF:

0.542

Gnomad OTH exome

AF:

0.586

GnomAD4 exome

AF:

0.552

AC:

802147

AN:

1453936

Hom.:

223348

Cov.:

AF XY:

0.552

AC XY:

398620

AN XY:

722690

show subpopulations

Gnomad4 AFR exome

AF:

0.334

Gnomad4 AMR exome

AF:

0.709

Gnomad4 ASJ exome

AF:

0.559

Gnomad4 EAS exome

AF:

0.691

Gnomad4 SAS exome

AF:

0.561

Gnomad4 FIN exome

AF:

0.570

Gnomad4 NFE exome

AF:

0.546

Gnomad4 OTH exome

AF:

0.548

GnomAD4 genome

AF:

0.508

AC:

77043

AN:

151698

Hom.:

20484

Cov.:

AF XY:

0.512

AC XY:

37976

AN XY:

74108

show subpopulations

Gnomad4 AFR

AF:

0.345

Gnomad4 AMR

AF:

0.646

Gnomad4 ASJ

AF:

0.558

Gnomad4 EAS

AF:

0.653

Gnomad4 SAS

AF:

0.579

Gnomad4 FIN

AF:

0.582

Gnomad4 NFE

AF:

0.546

Gnomad4 OTH

AF:

0.552

Alfa

AF:

0.544

Hom.:

47390

Bravo

AF:

0.508

TwinsUK

AF:

0.530

AC:

1965

ALSPAC

AF:

0.537

AC:

2068

ESP6500AA

AF:

0.355

AC:

1563

ESP6500EA

AF:

0.554

AC:

4762

ExAC

AF:

0.548

AC:

66395

Asia WGS

AF:

0.630

AC:

2190

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.047

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.66

CADD

Benign

9.3

DANN

Benign

0.43

DEOGEN2

Benign

0.065

T;.;.;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.16

T;T;T;T

MetaRNN

Benign

0.0000014

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-2.4

N;.;.;.

PrimateAI

Benign

0.43

PROVEAN

Benign

1.2

N;N;.;.

REVEL

Benign

0.029

Sift

Benign

1.0

T;T;.;.

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0

.;.;.;B

Vest4

0.063

MPC

0.14

ClinPred

0.0016

GERP RS

2.4

Varity_R

0.038

gMVP

0.075

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over