17-3664705-G-T

Position:

• chr17-3664705-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014604.4(TAX1BP3):​c.133C>A​(p.Pro45Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TAX1BP3 NM_014604.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.34

Genes affected

TAX1BP3 (HGNC:30684): (Tax1 binding protein 3) This gene encodes a small, highly conserved protein with a single PDZ domain. PDZ (PSD-95/Discs large/ZO-1 homologous) domains promote protein-protein interactions that affect cell signaling, adhesion, protein scaffolding, and receptor and ion transporter functions. The encoded protein interacts with a large number of target proteins that play roles in signaling pathways; for example, it interacts with Rho A and glutaminase L and also acts as a negative regulator of the Wnt/beta-catenin signaling pathway. This protein was first identified as binding to the T-cell leukaemia virus (HTLV1) Tax oncoprotein. Overexpression of this gene has been implicated in altered cancer cell adhesion, migration and metastasis. The encoded protein also modulates the localization and density of inwardly rectifying potassium channel 2.3 (Kir2.3). To date, this protein has been shown to play a role in cell proliferation, development, stress response, and polarization. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Apr 2017]

P2RX5-TAX1BP3 (HGNC:49191): (P2RX5-TAX1BP3 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring P2RX5 (purinergic receptor P2X, ligand-gated ion channel, 5) and TAX1BP3 (Tax1 binding protein 3) genes on chromosome 17. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Mar 2011]

P2RX5-TAX1BP3 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TAX1BP3	NM_014604.4	c.133C>A	p.Pro45Thr	missense_variant	2/4	ENST00000225525.4	NP_055419.1
TAX1BP3	NM_001204698.2	c.133C>A	p.Pro45Thr	missense_variant	2/3		NP_001191627.1
P2RX5-TAX1BP3	NR_037928.1	n.5188C>A		non_coding_transcript_exon_variant	13/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TAX1BP3	ENST00000225525.4	c.133C>A	p.Pro45Thr	missense_variant	2/4	1	NM_014604.4	ENSP00000225525.3
P2RX5-TAX1BP3	ENST00000550383.1	n.*3490C>A		non_coding_transcript_exon_variant	13/15	2		ENSP00000455681.1
P2RX5-TAX1BP3	ENST00000550383.1	n.*3490C>A		3_prime_UTR_variant	13/15	2		ENSP00000455681.1
TAX1BP3	ENST00000611779.4	c.133C>A	p.Pro45Thr	missense_variant	2/3	2		ENSP00000484776.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2022

The c.133C>A (p.P45T) alteration is located in exon 2 (coding exon 2) of the TAX1BP3 gene. This alteration results from a C to A substitution at nucleotide position 133, causing the proline (P) at amino acid position 45 to be replaced by a threonine (T). 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	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.077	.;T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.066	D
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	.;M
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.8	.;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0020	.;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.84
MutPred		0.52		Gain of phosphorylation at P45 (P = 0.0657);Gain of phosphorylation at P45 (P = 0.0657);
MVP		0.59
MPC		1.3
ClinPred		0.99	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.88
gMVP		0.61

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-3567999;