GeneBe

TBX3

protein-coding

T-box transcription factor 3, the group of T-box transcription factors

Gene summary

This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. This protein is a transcriptional repressor and is thought to play a role in the anterior/posterior axis of the tetrapod forelimb. Mutations in this gene cause ulnar-mammary syndrome, affecting limb, apocrine gland, tooth, hair, and genital development. Alternative splicing of this gene results in three transcript variants encoding different isoforms; however, the full length nature of one variant has not been determined. [provided by RefSeq, Jul 2008]

Previous symbols:
  • UMS

MANE transcript

NM_005996.4

Inheritance

AD

ClinVar variants

P:41U:318B:193

Top phenotype

Ulnar-Mammary syndrome

gnomAD constraint

pLI —, LoF o/e 0.09

Max pathogenic AF

—

Genomic locus

chr12:114,670,255-114,684,175

External References & Databases

Ensembl (ENSG00000135111)NCBI Gene (6926)OMIM (601621)HGNC:11602GenCCUniProt (O15119)AlphaFoldClinVar (TBX3)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~13.9 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

ulnar-mammary syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008411

Submitter: ClinGen

The *TBX3* gene is located on chromosome 12 at 12q24.21 and encodes T-box Transcription Factor 3 protein. *TBX3* is a transcription factor characterised by a T-box DNA-binding domain , a nuclear localization signal, two repression domains, and an activation domain. The *TBX3* transcription factor, either activator or repressor, plays a key role in the formation of structures such as the heart, limbs, mammary glands, and lungs during embryogenesis. *TBX3* was first reported in relation to autosomal dominant ulnar-mammary syndrome in 1997 (Bamshad et al 1997, PMID: 9207801). This condition is associated with posterior limb deficiencies or duplications, apocrine/mammary gland hypoplasia and/or dysfunction, abnormal dentition, delayed puberty in males, and genital anomalies. Bamshad et al. (1997) demonstrated variants in *TBX3* in 2 families with ulnar-mammary syndrome. Each variant (frameshift, splice donor site) was predicted to cause haploinsufficiency of *TBX3*, implying that critical levels of this transcription factor are required for morphogenesis of several organs. Evidence supporting this gene-disease relationship includes case-level and experimental data. X (give number) heterozygous variants (nonsense, frameshift) in *TBX3* that have been identified in at least 8 unrelated patients with clinical features suggestive of autosomal dominant ulnar-mammary syndrome are included in this curation (Bamshad et al., 1997, PMID: 9207801; Sasaki et al., 2002, PMID: 12116211; Joss et al., 2011. PMID: 21199695; Tanteles et al., 2017, PMID:28145909; Galazzi et al., 2018, PMID:30550377; Wollnik et al., 2002, PMID: 12668170; Meneghini et al., 2005, PMID 16530712; Zhang et al., 2023, PMID: 36937985). The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by biochemical function, gene expression, non-human model systems (mouse) (Khan et al., 2020, PMID: 31669645; Chapman et al., 1996, PMID: 8853987; Gibson-Brown et al., 1996, PMID:8798150; Davenport et al., 2003, PMID: 12668638; Jerome-Majewska et al., 2005, PMID: 16222716; Frank et al., 2013, PMID: 23844108; Emechebe et al., 2016, PMID: 27046536). In summary, there is definitive evidence supporting the relationship between *TBX3* and autosomal dominant ulnar-mammary syndrome (*TBX3*-related Ulnar-Mammary syndrome). This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date of April 22nd 2025 (SOP Version 11).

ulnar-mammary syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008411

Submitter: Labcorp Genetics (formerly Invitae)

heart conduction diseaseLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0000992

Submitter: Genomics England PanelApp

ulnar-mammary syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008411

Submitter: PanelApp Australia

ulnar-mammary syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008411

Submitter: Orphanet

ulnar-mammary syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008411

Submitter: G2P

Clinical Genomic Database (CGD)

Ulnar-Mammary syndromeAD

Manifestation: Cardiovascular; Dental; Endocrine; Genitourinary; Musculoskeletal; Renal

Intervention: Cardiovascular

Rationale: Cardiac anomalies, including arrhythmias, have been reported, and surveillance may allow early detection and management

Refs: 9207801; 12116211; 12668170; 19938096; 21199695; 28145909Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TBX3 variants in ClinVar

7 Conditions Cataloged
Ulnar-mammary syndromeTotal: 397
TBX3-related disorderTotal: 214
Inborn genetic diseasesTotal: 113
not providedTotal: 67
not specifiedTotal: 8
ObesityTotal: 1
Eccrine porocarcinomaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005996.4. 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.

EffectPLPVUSLBBSum
synonymous
3
clinvar
163
clinvar
11
clinvar
 177
missense
5
clinvar
308
clinvar
17
clinvar
2
clinvar
 332
nonsense
7
clinvar
1
clinvar
 8
start loss
1
clinvar
 1
frameshift
13
clinvar
10
clinvar
2
clinvar
 25
splice donor/acceptor (+/-2bp)
3
clinvar
3
clinvar
3
clinvar
 9
Total231831818013552

Highest pathogenic variant AF is 0.0000013743947

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 8 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_005996.4RefSeqNP_005987.37MANE Select
ENST00000349155.7EnsemblENSP00000257567.27MANE Select
NM_016569.4RefSeqNP_057653.38Standard
ENST00000257566.7EnsemblENSP00000257566.38Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
tbx3aDanio rerio

Structure: fin bud

Quality: aplastic

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human)
  • Mesodermal Commitment Pathway
  • Preimplantation Embryo

Biological Process

  • negative regulation of transcription by RNA polymerase II
  • skeletal system development
  • blood vessel development
  • in utero embryonic development
  • heart looping

Molecular Function

  • RNA polymerase II proximal promoter 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
  • DNA-binding transcription repressor activity, RNA polymerase II-specific

Cellular Component

  • nucleus

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000257566
Coding exons
8
Length
13911
Individuals with no LoFs
125744
Homozygous LoFs
0
Heterozygous LoFs
4
Defined
125748
p
0.0000159
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.733434460.7690.00002564767
Missense (PolyPhen)95168.680.563211900
Synonymous-0.8582162011.080.00001341520
Loss of Function4.00222.40.08920.00000109268

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000290.000029rare
Ashkenazi Jewish00.0absent
East Asian0.0000540.000054rare
Finnish00.0absent
European (Non-Finnish)0.00000880.0000088rare
South Asian0.0000380.000033rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Transcriptional repressor involved in developmental processes. Probably plays a role in limb pattern formation. Acts as a negative regulator of PML function in cellular senescence. {ECO:0000269|PubMed:10468588, ECO:0000269|PubMed:22002537}.;

Recessive Scores

pRec
0.191

Intolerance Scores

LoFtool
0.00413
RVIS EVS
-0.73
RVIS percentile EVS
14.08

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.975

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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