rs1046268

Positions:

• chr19-3750617-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.51 (20484 hom., cov: 31)
  • Exomes 𝑓: 0.55 (223348 hom.)
• Consequence: TJP3 NM_001267560.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.41

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]

ACMG classification

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/exons	MANE	UniProt
TJP3	NM_001267560.2	c.2693T>C	p.Met898Thr	missense_variant	21/21	ENST00000541714.7
TJP3	NM_001267561.2	c.2720T>C	p.Met907Thr	missense_variant	21/21
TJP3	XM_047438611.1	c.2891T>C	p.Met964Thr	missense_variant	21/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TJP3	ENST00000541714.7	c.2693T>C	p.Met898Thr	missense_variant	21/21	2	NM_001267560.2	P4

Frequencies

GnomAD3 genomes AF: 0.508 AC: 76964 AN: 151580 Hom.: 20461 Cov.: 31

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

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.: 48 AF XY: 0.552 AC XY: 398620 AN XY: 722690

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.: 31 AF XY: 0.512 AC XY: 37976 AN XY: 74108

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	T
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	N
LIST_S2	Benign	0.16	T;T;T;T
MetaRNN	Benign	0.0000014	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.4	N;.;.;.
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.43	T
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	T
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

Other links and lift over

dbSNP: rs1046268; hg19: chr19-3750615; COSMIC: COSV53662531; COSMIC: COSV53662531;