TBX4

T-box transcription factor 4, the group of T-box transcription factors

Basic information

Region (hg38): 17:61452404-61485110

Links

ENSG00000121075 ∙ NCBI:9496 ∙ OMIM:601719 ∙ HGNC:11603 ∙ Uniprot:P57082 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• coxopodopatellar syndrome (Strong), mode of inheritance: AD
• coxopodopatellar syndrome (Definitive), mode of inheritance: AD
• coxopodopatellar syndrome (Supportive), mode of inheritance: AD
• heritable pulmonary arterial hypertension (Supportive), mode of inheritance: AD
• pulmonary arterial hypertension (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Ischiocoxopodopatellar syndrome with or without pulmonary arterial hypertension	AD	Cardiovascular; Pulmonary	The condition can include pulmonary artery hypertension, and awareness may allow prompt diagnosis and management	Cardiovascular; Genitourinary; Musculoskeletal; Neurologic; Pulmonary	15106123; 23592887; 30413314; 31151956; 31761294

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TBX4 gene.

• not provided (15 variants)
• Coxopodopatellar syndrome (9 variants)
• Pulmonary hypertension, primary, 1 (4 variants)
• Autosomal recessive amelia (3 variants)
• 6 conditions (1 variants)
• Abnormality of prenatal development or birth (1 variants)
• Pulmonary hypertension, primary, 1;Coxopodopatellar syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TBX4 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			5	20	9	34
missense	3	4	62	10	7	86
nonsense	12	3				15
start loss		1				1
frameshift	5	12	2			19
inframe indel		1	6			7
splice donor/acceptor (+/-2bp)	3	2				5
splice region			1	3	1	5
non coding			10	5	27	42
Total	23	23	85	35	43

Highest pathogenic variant AF is 0.0000657

Variants in TBX4

This is a list of pathogenic ClinVar variants found in the TBX4 region.

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

Position	Type	Phenotype	Significance	ClinVar
17-61455901-C-G		TBX4-related disorder	Likely benign (Jun 14, 2023)
17-61455905-T-C			Likely benign (Jul 01, 2024)
17-61455907-G-A		Pulmonary hypertension, primary, 1	not provided (-)
17-61456493-G-A		Coxopodopatellar syndrome	Likely pathogenic (May 04, 2022)
17-61456506-G-A		Coxopodopatellar syndrome • TBX4-related disorder	Benign/Likely benign (Nov 01, 2023)
17-61456507-G-C		Coxopodopatellar syndrome	Benign (Feb 01, 2024)
17-61456513-C-T		Inborn genetic diseases	Uncertain significance (Aug 08, 2023)
17-61456514-C-T		Coxopodopatellar syndrome • TBX4-related disorder	Benign (Jan 12, 2018)
17-61456524-G-A			Uncertain significance (May 01, 2024)
17-61456527-GCCTTCCGGGC-G		Pulmonary arterial hypertension • Pulmonary hypertension, primary, 1	Likely pathogenic (-)
17-61456530-T-C		TBX4-related disorder	Uncertain significance (Jun 15, 2024)
17-61456537-C-T		Coxopodopatellar syndrome	Uncertain significance (Jan 13, 2018)
17-61456542-GGCCCAGCGCTCGGAGAGGCCA-G			Uncertain significance (Jan 19, 2022)
17-61456554-G-T		Pulmonary hypertension, primary, 1	Pathogenic (May 18, 2023)
17-61456561-C-T			Benign (Apr 21, 2022)
17-61456581-G-A			Uncertain significance (Sep 21, 2023)
17-61456584-C-G			Uncertain significance (May 08, 2023)
17-61456587-G-T		Inborn genetic diseases	Uncertain significance (Dec 01, 2022)
17-61456594-C-T		Coxopodopatellar syndrome	Benign (Jun 01, 2024)
17-61456598-G-T		Coxopodopatellar syndrome	Uncertain significance (Jan 12, 2018)
17-61456600-C-T		Coxopodopatellar syndrome • Inborn genetic diseases	Uncertain significance (Jan 03, 2024)
17-61456600-C-CG		Coxopodopatellar syndrome	not provided (-)
17-61456611-G-T		Pulmonary arterial hypertension	Likely pathogenic (-)
17-61456615-C-A		Inborn genetic diseases	Uncertain significance (Oct 10, 2023)
17-61456627-G-GC		Pulmonary hypertension, primary, 1	not provided (-)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TBX4	protein_coding	protein_coding	ENST00000240335	8	32707

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.505	0.495	125731	0	17	125748	0.0000676

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.871	269	312	0.861	0.0000190	3537
Missense in Polyphen		95	134.4	0.70683		1579
Synonymous	-0.687	145	135	1.08	0.00000914	1103
Loss of Function	3.55	5	23.6	0.211	0.00000147	249

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000177	0.000177
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000705	0.0000703
Middle Eastern	0.00	0.00
South Asian	0.0000980	0.0000980
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Involved in the transcriptional regulation of genes required for mesoderm differentiation. Probably plays a role in limb pattern formation.
• Disease: DISEASE: Ischiocoxopodopatellar syndrome (ICPPS) [MIM:147891]: An autosomal dominant bone disease characterized by patellar aplasia or hypoplasia and by anomalies of the pelvis and feet, including disrupted ossification of the ischia and inferior pubic rami. {ECO:0000269|PubMed:15106123}. Note=The disease is caused by mutations affecting the gene represented in this entry.

Recessive Scores

• pRec: 0.146

Intolerance Scores

• loftool: 0.109
• rvis_EVS: -0.58
• rvis_percentile_EVS: 18.78

Haploinsufficiency Scores

• pHI: 0.867
• hipred: Y
• hipred_score: 0.752
• ghis: 0.562

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.790

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Tbx4
• 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; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); limbs/digits/tail phenotype; skeleton phenotype; homeostasis/metabolism phenotype; cellular phenotype; growth/size/body region phenotype

Zebrafish Information Network

• Gene name: tbx4
• Affected structure: pelvic fin skeleton
• Phenotype tag: abnormal
• Phenotype quality: absent

Gene ontology

• Biological process: angiogenesis;morphogenesis of an epithelium;regulation of transcription, DNA-templated;regulation of transcription by RNA polymerase II;multicellular organism development;lung development;embryonic limb morphogenesis;limb morphogenesis;skeletal system morphogenesis
• Cellular component: nucleus
• Molecular function: DNA-binding transcription factor activity, RNA polymerase II-specific;DNA binding;DNA-binding transcription factor activity