NM_001330239.4:c.4843C>G

Variant names:

• chr15-29708566-G-C
• rs2042046744
• NM_001330239.4:c.4843C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001330239.4(TJP1):​c.4843C>G​(p.Pro1615Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TJP1 NM_001330239.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.73
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2918262).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TJP1	NM_001330239.4	c.4843C>G	p.Pro1615Ala	missense_variant	Exon 25 of 28	ENST00000614355.5	NP_001317168.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TJP1	ENST00000614355.5	c.4843C>G	p.Pro1615Ala	missense_variant	Exon 25 of 28	5	NM_001330239.4	ENSP00000483470.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 11, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4843C>G (p.P1615A) alteration is located in exon 25 (coding exon 25) of the TJP1 gene. This alteration results from a C to G substitution at nucleotide position 4843, causing the proline (P) at amino acid position 1615 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;T;.;T;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.29	T;T;T;T;T
MetaSVM	Uncertain	0.61	D
MutationAssessor	Benign	1.9	L;.;.;.;.
PhyloP100		7.7
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.6	D;D;D;.;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0020	D;D;D;.;D
Sift4G	Benign	0.15	T;T;T;T;T
Polyphen		0.99	D;B;.;.;D
Vest4		0.44
MVP		0.21
MPC		0.10
ClinPred		0.93	D
GERP RS		5.1
PromoterAI		-0.0080	Neutral
Varity_R		0.36
gMVP		0.44
Mutation Taster		=75/25	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: rs2042046744; hg19: chr15-30000770;