TBXAS1
protein-codingthromboxane A synthase 1, the group of Cytochrome P450 family 5
Gene summary
This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. However, this protein is considered a member of the cytochrome P450 superfamily on the basis of sequence similarity rather than functional similarity. This endoplasmic reticulum membrane protein catalyzes the conversion of prostglandin H2 to thromboxane A2, a potent vasoconstrictor and inducer of platelet aggregation. The enzyme plays a role in several pathophysiological processes including hemostasis, cardiovascular disease, and stroke. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~243.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009274
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009274
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009274
Submitter: ClinGen
The TBXAS1 gene encodes thromboxane synthase, a cytochrome P450 enzyme, that catalyzes the conversion of the prostaglandin endoperoxide into thromboxane A2, a potent vasoconstrictor and inducer of platelet aggregation playing a crucial role in hemostasis. TBXAS1 was first reported in relation to Ghosal hematodiaphyseal syndrome (GHDD) in 2008 (Genevieve et al, PMID 18264100) in 4 families with diaphyseal dysplasia, increased bone density, anemia, thrombocytopenia, decreased TXB2 levels and increased PGE2 levels. Platelet aggregation was studied in one member of one family and resulted impaired in response to arachidonic acid. None of the patients showed bleeding symptoms. 10 unique variants have been reported in humans, 8 missense, 2 frameshift and 1 stop. Evidence supporting this gene-disease relationship includes genetic evidences (case-level data) and experimental evidences (functional evidence of protein expression, biochemical function, non-human model organisms). Summary of Case Level Data: 9.4 POINTS Variants in this gene have been reported in 20 GHDD probands in 11 publications (PMIDs 18264100, 27156553, 28868793, 33244729, 33595912, 35395429, 36574346, 38497148, 39220787 , 38873830, 39277773) leading to a score of 9.4 for genetic evidence. The mechanism for disease is homozygous loss of function. Summary of Experimental Data: 3 POINTS This gene-disease association is supported by evidences of Biochemical Function (B): in human and horse platelet microsomes a molecule that converted prostaglandin endoperoxides into TXA2 was found. This molecule was ascertained to be thromboxane synthase (PMID 934294). Evidence of protein expression (A): Thromboxane synthase was purified from human platelets a close analogy to the group of cytochrome P-450 proteins was established. The purified enzyme catalyzed the formation of the stable end product thromboxane B2 from its substrate prostaglandin H2 (PMID: 2999104). A mouse model knockout for TBXAS1 showed similarities but also differences from GHDD patients: the mouse model showed a lack of platelet aggregation in response to arachidonic acid and a defect in TXA2 production, compatible with patients with GHDD. However, patients with GHDD do not have any bleeding problem while the TXAS-/- mouse show increased bleeding time, moreover the mouse model do not show increased bone density, myelophthisic anemia, leukopenia and thrombocytopenia (PMID: 15010374). It is worth noting that a disease called “Thromboxane Synthase deficiency” (OMIM 614158) was described. Patients show bleeding, impaired aggregation in response to arachidonic acid but normal aggregation in response to the thromboxane analogue U46619, decreased serum TXB2, phenotypes compatible with a deficiency of Thromboxane Synthase (Weiss et al PMID 66560, Mestel et al PMID 6101498, Defreyn et al PMID 6268139). However, DNA analysis was not carried out in these patients and we can not establish an association with variants in TBXAS1. In summary, we found definitive association of TBXAS1 with Ghosal hematodiaphyseal syndrome. This gene-disease pair was originally approved by the HT GCEP on 10/28/2020. As a result of the 2023 reevaluation new genetic evidence was identified (PMIDs: 33244729, 33595912, 35395429, 36574346) but the classification remained at Moderate (SOP Version 9). This classification was approved by the ClinGen Hemostasis Thrombosis Working Group on 06/07/2023 (SOP Version 9). As a result of the current reevaluation new genetic evidence was identified (PMIDs: 38497148, 39220787 , 38873830, 39277773) and the classification is Definitive. This classification was approved by the ClinGen Hemostasis Thrombosis Working Group on 2025 Apr 07 (SOP Version 11).
Inheritance Pattern: AR
Disease ID:MONDO:0009274
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0009274
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Hematologic; Musculoskeletal; Neurologic
Intervention: Hematologic
Rationale: Steroid therapy has been described as effective for some hematologic manifestations
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to TBXAS1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001061.7. 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 | 4 | 68 | 8 | 80 | ||
| missense | 2 | 5 | 142 | 24 | 7 | 180 |
| nonsense | 4 | 2 | 2 | 8 | ||
| start loss | 1 | 1 | 2 | |||
| frameshift | 9 | 4 | 5 | 18 | ||
| splice donor/acceptor (+/-2bp) | 7 | 2 | 9 | |||
| Total | 15 | 18 | 156 | 93 | 15 | 297 |
Highest pathogenic variant AF is 0.00035641718
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001052.3 | 13 | MANE Select | |
| Ensembl | ENSP00000402536.3 | 13 | MANE Select | |
| RefSeq | NP_001124438.2 | 13 | Standard | |
| RefSeq | NP_001159725.2 | 14 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| tbxas1 | Danio rerio | Structure: cardiac muscle cell Quality: shape abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Platelet activation - Homo sapiens (human)
- Arachidonic acid metabolism - Homo sapiens (human)
- Phenytoin Pathway, Pharmacokinetics
- Celecoxib Pathway, Pharmacodynamics
- Platelet Aggregation Inhibitor Pathway, Pharmacodynamics
Biological Process
- icosanoid metabolic process
- cyclooxygenase pathway
- oxidation-reduction process
Molecular Function
- monooxygenase activity
- thromboxane-A synthase activity
- iron ion binding
- oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen
- heme binding
Cellular Component
- endoplasmic reticulum membrane
- integral component of membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000416849
- Coding exons
- 14
- Length
- 243276
- Individuals with no LoFs
- 125599
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 149
- Defined
- 125748
- p
- 0.000593
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.807 | 381 | 339 | 1.12 | 0.0000216 | 3788 |
| Missense (PolyPhen) | 142 | 113.69 | 1.249 | 1302 | ||
| Synonymous | -1.21 | 155 | 137 | 1.13 | 0.00000927 | 1162 |
| Loss of Function | -0.133 | 30 | 29.2 | 1.03 | 0.00000154 | 341 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.0014 | 0.0014 | notable |
| Latino/Admixed American | 0.00058 | 0.00058 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.0018 | 0.0018 | notable |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00040 | 0.00040 | rare |
| South Asian | 0.00085 | 0.00085 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Disease
- DISEASE: Note=Thromboxane synthetase deficiency has been detected in some patients with a bleeding disorder due to platelet dysfunction. {ECO:0000269|PubMed:6101498}.;
Recessive Scores
- pRec
- 0.321
Intolerance Scores
- LoFtool
- 0.983
- RVIS EVS
- 0.94
- RVIS percentile EVS
- 89.87
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.936
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |