17-3664679-C-A

Variant summary

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

The NM_014604.4(TAX1BP3):c.159G>T(p.Lys53Asn) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000116 in 1,461,488 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: TAX1BP3 NM_014604.4 missense, splice_region
• Scores: Splicing: ADA: 0.9995
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.47

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:):

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	UniProt
TAX1BP3	NM_014604.4	c.159G>T	p.Lys53Asn	missense_variant, splice_region_variant	2/4	ENST00000225525.4
P2RX5-TAX1BP3	NR_037928.1	n.5214G>T		splice_region_variant, non_coding_transcript_exon_variant	13/15
TAX1BP3	NM_001204698.2	c.159G>T	p.Lys53Asn	missense_variant, splice_region_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAX1BP3	ENST00000225525.4	c.159G>T	p.Lys53Asn	missense_variant, splice_region_variant	2/4	1	NM_014604.4	P1
TAX1BP3	ENST00000611779.4	c.159G>T	p.Lys53Asn	missense_variant, splice_region_variant	2/3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 250700 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135644

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461488 Hom.: 0 Cov.: 30 AF XY: 0.0000151 AC XY: 11 AN XY: 727014

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 12, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant has not been reported in the literature in individuals affected with TAX1BP3-related conditions. This variant is present in population databases (rs375177174, gnomAD 0.002%). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 53 of the TAX1BP3 protein (p.Lys53Asn). This variant also falls at the last nucleotide of exon 2, which is part of the consensus splice site for this exon. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.47
Cadd	Pathogenic	32
Dann	Uncertain	0.99
Eigen	Benign	-0.025
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.49	T;D
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.82	D
Sift4G	Uncertain	0.027	D;T
Polyphen		0.26	.;B
Vest4		0.73
MutPred		0.39		Loss of ubiquitination at K53 (P = 0.0071);Loss of ubiquitination at K53 (P = 0.0071);
MVP		0.34
MPC		1.3
ClinPred		0.62	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.67
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.10		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: rs375177174; hg19: chr17-3567973;