TBXT

protein-coding

T-box transcription factor T, the group of T-box transcription factors

Gene summary

The protein encoded by this gene is an embryonic nuclear transcription factor that binds to a specific DNA element, the palindromic T-site. It binds through a region in its N-terminus, called the T-box, and effects transcription of genes required for mesoderm formation and differentiation. The protein is localized to notochord-derived cells. Variation in this gene was associated with susceptibility to neural tube defects and chordoma. A mutation in this gene was found in a family with sacral agenesis with vertebral anomalies. [provided by RefSeq, Sep 2018]

Previous symbols:

MANE transcript

NM_001366285.2

Inheritance

AR, AD

ClinVar variants

P:2U:44B:14

Top phenotype

Chordoma, susceptibility to

gnomAD constraint

pLI —, LoF o/e 0.33

Max pathogenic AF

—

Genomic locus

chr6:166,157,656-166,168,700

External References & Databases

Ensembl (ENSG00000164458)

Transcript & Mutation Effects

hg38 • Region Span ~11.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

sacral agenesis-abnormal ossification of the vertebral bodies-persistent notochordal canal syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014314

Submitter: Orphanet

chordomaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008978

Submitter: Genomics England PanelApp

sacral agenesis-abnormal ossification of the vertebral bodies-persistent notochordal canal syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014314

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Chordoma, susceptibility toAD

Manifestation: Gastrointestinal; Musculoskeletal; Oncologic; Renal

Intervention: Oncologic

Rationale: Surveillance for neoplasms could potentially be beneficial in order to allow early detection and treatment

Refs: 8733136; 10204846; 10332959; 10817656; 12116228; 15449172; 19801981; 23064415; 24253444

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TBXT variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 39

not providedTotal: 11

TBXT-related disorderTotal: 11

Sacral agenesis-abnormal ossification of the vertebral bodies-persistent notochordal canal syndromeTotal: 8

Neural tube defects, susceptibility toTotal: 5

Neural tube defectTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001366285.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				8 clinvar	2 clinvar	10
missense	1 clinvar		42 clinvar	3 clinvar	1 clinvar	47
nonsense			1 clinvar			1
start loss						0
frameshift		1 clinvar	1 clinvar			2
splice donor/acceptor (+/-2bp)						0
Total	1	1	44	11	3	60

Highest pathogenic variant AF is 6.8404785e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 14 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001366285.2	RefSeq	NP_001353214.1	8	MANE Select
ENST00000366876.7	Ensembl	ENSP00000355841.3	8	MANE Select
NM_001270484.2	RefSeq	NP_001257413.1	7	Standard
NM_001366286.2	RefSeq	NP_001353215.1	8	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
tbxta	Danio rerio	Structure: Rohon-Beard neuron Quality: increased amount abnormal

Gene / Model

Organism

Observed Phenotype

tbxta

Danio rerio

Structure: Rohon-Beard neuron

Quality: increased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cardiac Progenitor Differentiation
Regulation of nuclear beta catenin signaling and target gene transcription
Validated transcriptional targets of deltaNp63 isoforms

Biological Process

negative regulation of transcription by RNA polymerase II
vasculogenesis
somitogenesis
neural plate morphogenesis
neural tube closure

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
RNA polymerase II distal enhancer sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
RNA polymerase II transcription factor binding
RNA polymerase II activating transcription factor binding

Cellular Component

nuclear chromatin
nucleus
cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000296946
Coding exons: 8
Length: 11045
Individuals with no LoFs: 125740
Homozygous LoFs: 0
Heterozygous LoFs: 8
Defined: 125748
p: 0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.984	207	251	0.825	0.0000139	2837
Missense (PolyPhen)		43	70.443	0.61043		896
Synonymous	0.232	106	109	0.972	0.00000724	878
Loss of Function	2.64	6	18.1	0.331	7.88e-7	203

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000027	0.000026	rare
South Asian	0.000033	0.000033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the transcriptional regulation of genes required for mesoderm formation and differentiation. Binds to a palindromic site (called T site) and activates gene transcription when bound to such a site. {ECO:0000250|UniProtKB:P20293}.;
Disease: DISEASE: Chordoma (CHDM) [MIM:215400]: Rare, clinically malignant tumors derived from notochordal remnants. They occur along the length of the spinal axis, predominantly in the sphenooccipital, vertebral and sacrococcygeal regions. They are characterized by slow growth, local destruction of bone, extension into adjacent soft tissues and rarely, distant metastatic spread. {ECO:0000269|PubMed:19801981}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Susceptibility to development of chordomas is due to a T gene duplication.; DISEASE: Sacral agenesis with vertebral anomalies (SAVA) [MIM:615709]: A disorder characterized by abnormalities of the spine, including sacral agenesis, abnormal ossification of all vertebral bodies, and a persistent notochordal canal during development. {ECO:0000269|PubMed:24253444}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.276

Intolerance Scores

RVIS EVS: 0.69
RVIS percentile EVS: 85.18

Essentials

Essential (gene trap): N