NM_001267560.2:c.2296C>T

Variant names:

• chr19-3746850-C-T
• rs35335659
• NM_001267560.2:c.2296C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

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. 12/21 in silico tools predict 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
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.21
• Publications: 3 publications found

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

Our verdict: Benign. The variant received -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 VariationId is 2649010.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267560.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TJP3	NM_001267560.2	MANE Select	c.2296C>T	p.Arg766Trp	missense	Exon 18 of 21	NP_001254489.1	O95049-1
	TJP3	NM_001267561.2		c.2323C>T	p.Arg775Trp	missense	Exon 18 of 21	NP_001254490.1	O95049-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TJP3	ENST00000541714.7	TSL:2 MANE Select	c.2296C>T	p.Arg766Trp	missense	Exon 18 of 21	ENSP00000439278.1	O95049-1
	TJP3	ENST00000587686.1	TSL:1	c.2353C>T	p.Arg785Trp	missense	Exon 17 of 20	ENSP00000467864.1	O95049-3
	TJP3	ENST00000589378.5	TSL:2	c.2323C>T	p.Arg775Trp	missense	Exon 18 of 21	ENSP00000465419.1	O95049-4

Frequencies

GnomAD3 genomes AF: 0.00297 AC: 444 AN: 149744 Hom.: 3 Cov.: 32

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

GnomAD2 exomes AF: 0.000750 AC: 182 AN: 242666 AF XY: 0.000571

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 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.: 2 Cov.: 36 AF XY: 0.000274 AC XY: 191 AN XY: 697104

African (AFR) AF: 0.0107 AC: 339 AN: 31538

American (AMR) AF: 0.000870 AC: 37 AN: 42536

Ashkenazi Jewish (ASJ) AF: 0.0000421 AC: 1 AN: 23734

East Asian (EAS) AF: 0.00 AC: 0 AN: 35352

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84912

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46662

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5422

European-Non Finnish (NFE) AF: 0.0000353 AC: 38 AN: 1075448

Other (OTH) AF: 0.000516 AC: 29 AN: 56186

GnomAD4 genome AF: 0.00296 AC: 443 AN: 149864 Hom.: 3 Cov.: 32 AF XY: 0.00279 AC XY: 204 AN XY: 73234

African (AFR) AF: 0.0100 AC: 412 AN: 41152

American (AMR) AF: 0.00146 AC: 22 AN: 15098

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3444

East Asian (EAS) AF: 0.00 AC: 0 AN: 4900

South Asian (SAS) AF: 0.00 AC: 0 AN: 4516

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10034

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000593 AC: 4 AN: 67438

Other (OTH) AF: 0.00238 AC: 5 AN: 2098

Alfa AF: 0.00159 Hom.: 1

Bravo AF: 0.00320

ESP6500AA AF: 0.00954 AC: 42

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000965 AC: 117

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Benign	0.045
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.33	N
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.2
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.042
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.31
MVP		0.46
MPC		0.25
ClinPred		0.037	T
GERP RS		1.2
Varity_R		0.26
gMVP		0.38
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs35335659; hg19: chr19-3746848;