TBX5

T-box transcription factor 5, the group of T-box transcription factors

Basic information

Region (hg38): 12:114353911-114408442

Previous symbols: [ "HOS" ]

Links

ENSG00000089225 ∙ NCBI:6910 ∙ OMIM:601620 ∙ HGNC:11604 ∙ Uniprot:Q99593 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Holt-Oram syndrome (Definitive), mode of inheritance: AD
• heart conduction disease (Moderate), mode of inheritance: AD
• Holt-Oram syndrome (Supportive), mode of inheritance: AD
• Holt-Oram syndrome (Definitive), mode of inheritance: AD
• Holt-Oram syndrome (Strong), mode of inheritance: AD
• Holt-Oram syndrome (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Holt-Oram syndrome	AD	Cardiovascular	While the condition may be recognizable in the majority, individuals may have cardiac conduction abnormalities even without known cardiac malformations, and surveillance (eg, with electrocardiography) may allow early detection and management	Cardiovascular; Musculoskeletal	14402857; 8730285; 8911604; 8988165; 8988164; 10077612; 10842287; 12818525; 17366586; 18818409; 20301290

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TBX5 gene.

• Aortic valve disease 2 (52 variants)
• not provided (31 variants)
• Holt-Oram syndrome (16 variants)
• Cardiovascular phenotype (3 variants)
• TBX5-related disorder (2 variants)
• Heart, malformation of (1 variants)
• Atrial septal defect, ostium secundum type;Ventricular septal defect;Mitral regurgitation (1 variants)
• Left ventricular noncompaction cardiomyopathy;Holt-Oram syndrome (1 variants)
• Primary dilated cardiomyopathy (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TBX5 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous	1		5	111	5	122
missense	10	11	183	25	1	230
nonsense	24	5	2	1		32
start loss						0
frameshift	42	6	2			50
inframe indel		2	1			3
splice donor/acceptor (+/-2bp)	11	5				16
splice region			6	8	1	15
non coding		1	34	27	52	114
Total	88	30	227	164	58

Highest pathogenic variant AF is 0.0000197

Variants in TBX5

This is a list of pathogenic ClinVar variants found in the TBX5 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
12-114353984-G-A		Holt-Oram syndrome	Uncertain significance (Jan 12, 2018)
12-114354021-C-T		Holt-Oram syndrome	Uncertain significance (Aug 18, 2021)
12-114354051-CACTT-C		Holt-Oram syndrome	Likely benign (Jun 14, 2016)
12-114354086-A-C		Holt-Oram syndrome	Uncertain significance (Jan 13, 2018)
12-114354146-GA-G		Holt-Oram syndrome	Benign (Jun 14, 2016)
12-114354159-C-A		Holt-Oram syndrome	Benign (Jan 12, 2018)
12-114354188-C-T		Holt-Oram syndrome	Uncertain significance (Jan 12, 2018)
12-114354201-A-C		Holt-Oram syndrome	Benign (Jan 13, 2018)
12-114354336-A-G		Holt-Oram syndrome	Uncertain significance (Jan 13, 2018)
12-114354344-A-G		Holt-Oram syndrome	Benign (Jan 13, 2018)
12-114354421-A-G		Holt-Oram syndrome	Uncertain significance (Jan 12, 2018)
12-114354431-T-C		Holt-Oram syndrome	Benign (Jan 11, 2019)
12-114354461-G-A		Holt-Oram syndrome	Uncertain significance (Aug 12, 2021)
12-114354572-T-C		Holt-Oram syndrome	Benign (Jan 13, 2018)
12-114354606-A-G		Holt-Oram syndrome	Uncertain significance (Jan 12, 2018)
12-114354623-T-C		Holt-Oram syndrome	Benign (Jan 13, 2018)
12-114354657-T-G		Holt-Oram syndrome	Uncertain significance (Jan 13, 2018)
12-114354676-A-T		Holt-Oram syndrome	Uncertain significance (Jan 12, 2018)
12-114354680-G-A		Holt-Oram syndrome	Uncertain significance (Jan 13, 2018)
12-114354696-T-G		Holt-Oram syndrome	Likely benign (Jan 13, 2018)
12-114354720-G-A		Holt-Oram syndrome	Benign (Jan 12, 2018)
12-114354726-G-C		Holt-Oram syndrome	Uncertain significance (Jan 13, 2018)
12-114354737-C-A		Holt-Oram syndrome	Uncertain significance (Jan 12, 2018)
12-114354773-TGGCA-CCAGCTGAATAAGAGCCCAGCATCTTATTC		Holt-Oram syndrome	Uncertain significance (Jun 14, 2016)
12-114354793-A-G		Holt-Oram syndrome	Benign (Jan 13, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TBX5	protein_coding	protein_coding	ENST00000310346	8	54512

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.000463	125556	0	2	125558	0.00000796

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.19	234	291	0.803	0.0000153	3423
Missense in Polyphen		49	81.032	0.6047		997
Synonymous	-3.44	170	122	1.40	0.00000717	1004
Loss of Function	4.35	0	22.1	0.00	0.00000103	254

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000579	0.0000579
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: DNA-binding protein that regulates the transcription of several genes and is involved in heart development and limb pattern formation (PubMed:25725155, PubMed:25963046, PubMed:29174768, PubMed:26917986, PubMed:27035640, PubMed:8988164). Binds to the core DNA motif of NPPA promoter (PubMed:26926761). {ECO:0000269|PubMed:25725155, ECO:0000269|PubMed:25963046, ECO:0000269|PubMed:26917986, ECO:0000269|PubMed:26926761, ECO:0000269|PubMed:27035640, ECO:0000269|PubMed:29174768, ECO:0000269|PubMed:8988164}.
• Disease: DISEASE: Holt-Oram syndrome (HOS) [MIM:142900]: Developmental disorder affecting the heart and upper limbs. It is characterized by thumb anomaly and atrial septal defects. {ECO:0000269|PubMed:10077612, ECO:0000269|PubMed:10842287, ECO:0000269|PubMed:12818525, ECO:0000269|PubMed:15735645, ECO:0000269|PubMed:20450920, ECO:0000269|PubMed:8988164, ECO:0000269|PubMed:8988165}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Defects in TBX5 are associated with susceptibility to heart disorders including dilated cardiomyopathy (DCM) and atrial fibrillation (AF). DCM is characterized by ventricular and impaired systolic function, resulting in heart failure and arrhythmia. Patient are at risk of premature death. AF is a common sustained cardiac rhythm disturbance. AF is characterized by disorganized atrial electrical activity and ineffective atrial contraction promoting blood stasis in the atria and reduces ventricular filling. It can result in palpitations, syncope, thromboembolic stroke, and congestive heart failure. {ECO:0000269|PubMed:25725155, ECO:0000269|PubMed:25963046, ECO:0000269|PubMed:26917986, ECO:0000269|PubMed:27035640}.
• Pathway: Heart Development;Cardiac Progenitor Differentiation;Gene expression (Transcription);Generic Transcription Pathway;RNA Polymerase II Transcription;YAP1- and WWTR1 (TAZ)-stimulated gene expression (Consensus)

Recessive Scores

• pRec: 0.209

Intolerance Scores

• rvis_EVS: -0.55
• rvis_percentile_EVS: 19.8

Haploinsufficiency Scores

• pHI: 0.825
• hipred: Y
• hipred_score: 0.837
• ghis: 0.474

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.937

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Tbx5
• Phenotype: growth/size/body region phenotype; muscle phenotype; homeostasis/metabolism phenotype; skeleton phenotype; embryo phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); normal phenotype; limbs/digits/tail phenotype

Zebrafish Information Network

• Gene name: tbx5a
• Affected structure: cardiac muscle cell
• Phenotype tag: abnormal
• Phenotype quality: dissociated from

Gene ontology

• Biological process: morphogenesis of an epithelium;bundle of His development;atrioventricular valve morphogenesis;endocardial cushion development;cardiac left ventricle formation;ventricular septum development;transcription initiation from RNA polymerase II promoter;cell-cell signaling;pattern specification process;heart development;negative regulation of cell population proliferation;negative regulation of epithelial to mesenchymal transition;lung development;embryonic limb morphogenesis;negative regulation of cell migration;embryonic forelimb morphogenesis;forelimb morphogenesis;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;positive regulation of cardioblast differentiation;cardiac muscle cell differentiation;pericardium development;negative regulation of cardiac muscle cell proliferation;positive regulation of cardiac muscle cell proliferation;atrial septum morphogenesis;cell migration involved in coronary vasculogenesis;positive regulation of secondary heart field cardioblast proliferation
• Cellular component: nucleus;nucleoplasm;cytoplasm;protein-containing complex;protein-DNA complex
• Molecular function: RNA polymerase II proximal promoter sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;DNA-binding transcription activator activity, RNA polymerase II-specific;DNA binding;DNA-binding transcription factor activity;protein binding;transcription factor binding;sequence-specific DNA binding