Genetic Variant NM_001330239.4:c.2368A>T (chr15-29726423-T-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001330239.4(TJP1):c.2368A>T(p.Ile790Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I790V) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Consequence

TJP1
NM_001330239.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.82

Publications

0 publications found

Variant links:

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

TJP1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.882

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330239.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TJP1	NM_001330239.4	MANE Select	c.2368A>T	p.Ile790Phe	missense	Exon 18 of 28	NP_001317168.1	A0A087X0K9
TJP1	NM_001301025.3		c.2647A>T	p.Ile883Phe	missense	Exon 19 of 29	NP_001287954.2	G3V1L9
TJP1	NM_001355012.2		c.2647A>T	p.Ile883Phe	missense	Exon 19 of 29	NP_001341941.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TJP1	ENST00000614355.5	TSL:5 MANE Select	c.2368A>T	p.Ile790Phe	missense	Exon 18 of 28	ENSP00000483470.2	A0A087X0K9
TJP1	ENST00000346128.10	TSL:1	c.2368A>T	p.Ile790Phe	missense	Exon 18 of 28	ENSP00000281537.7	Q07157-1
TJP1	ENST00000400011.6	TSL:1	c.2380A>T	p.Ile794Phe	missense	Exon 19 of 28	ENSP00000382890.2	G5E9E7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Benign

-0.045

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.36

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.045

MetaRNN

Pathogenic

0.88

MetaSVM

Benign

-0.55

MutationAssessor

Uncertain

2.9

PhyloP100

2.8

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.7

REVEL

Uncertain

0.30

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

0.99

Vest4

0.77

MutPred

0.66

Gain of catalytic residue at I790 (P = 0.0116)

MVP

0.31

MPC

1.6

ClinPred

0.99

GERP RS

3.5

Varity_R

0.93

gMVP

0.74

Mutation Taster

=56/44

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over