CTPS1
protein-codingCTP synthase 1, the group of Glutamine amidotransferase class 1 domain containing
Gene summary
This gene encodes an enzyme responsible for the catalytic conversion of UTP (uridine triphosphate) to CTP (cytidine triphospate). This reaction is an important step in the biosynthesis of phospholipids and nucleic acids. Activity of this proten is important in the immune system, and loss of function of this gene has been associated with immunodeficiency. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]
- CTPS
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~33.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014391
Submitter: ClinGen
*CTPS1* was first reported in relation to combined immunodeficiency due to CTPS1 deficiency in 2014 (Martin et al., PMID: 24870241). The enzyme (cytidine-5-prime-triphosphate synthetase) is encoded by the CTPS1 gene, and important in the biosynthesis of phospholipids and nucleic acids, and plays a key role in cell growth, development, and tumorigenesis. Only one unique nonsense variant (e.g. splice acceptor) has been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, and experimental data. Variants in this gene have been reported in at least 10 probands in 3 publications (PMIDs: 35983265, 24870241, 27638562). This gene-disease relationship is supported by mouse animal models (PMID: 38438357). Deletion of Ctps1 in T cells or treatment with a CTPS1 inhibitor rescued Foxp3-deficient mice from fatal systemic autoimmunity and reduced the severity of experimental autoimmune encephalomyelitis. De novo synthesis of impaired expansion of T and B cell findings support that CTPS1 may represent a target for immune suppression. This gene-disease relationship is also supported by experimental evidence (e.g. expression studies) (PMIDs: 32161190, 24870241). Proliferation and IL-2 secretion by T cells in response to TCR activation were markedly decreased in all patients, while other T cell effector functions were preserved. Another functional study showed CTPS1 expression was found to be low in resting T cells, but rapidly upregulated following TCR activation. These results highlight a key and specific role of CTPS1 in the immune system by its capacity to sustain the proliferation of activated lymphocytes during the immune response. In summary, there is definitive evidence to support the relationship between CTPS1 and autosomal recessive combined immunodeficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached.
Inheritance Pattern: AR
Disease ID:MONDO:0014391
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014391
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Oncologic
Intervention: Allergy/Immunology/Infectious; Oncologic
Rationale: Individuals are susceptible to frequent and severe viral and bacterial infections (as well as sequelae such as EBV-related lymphoma), and and antiinfectious prophylaxis and early and aggressive treatment of infections, as well as awareness of potential oncologic sequelae, may be beneficial; HSCT has been described
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CTPS1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001905.4. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 6 | 99 | 2 | 107 | ||
| missense | 116 | 4 | 120 | |||
| nonsense | 1 | 1 | ||||
| start loss | 1 | 1 | ||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 5 | 6 | |||
| Total | 1 | 0 | 130 | 103 | 2 | 236 |
Highest pathogenic variant AF is 0.00056350336
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001896.2 | 17 | MANE Select | |
| Ensembl | ENSP00000497602.1 | 17 | MANE Select | |
| RefSeq | NP_001288166.1 | 14 | Standard | |
| Ensembl | ENSP00000361699.1 | 17 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Pyrimidine metabolism - Homo sapiens (human)
- Pyrimidine Metabolism
- UMP Synthase Deiciency (Orotic Aciduria)
- Gemcitabine Action Pathway
- MNGIE (Mitochondrial Neurogastrointestinal Encephalopathy)
Biological Process
- nucleobase-containing compound metabolic process
- CTP biosynthetic process
- glutamine metabolic process
- nucleobase-containing small molecule interconversion
- pyrimidine nucleobase biosynthetic process
Molecular Function
- CTP synthase activity
- ATP binding
- identical protein binding
Cellular Component
- cytoplasm
- cytosol
- membrane
- cytoophidium
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000372621
- Coding exons
- 17
- Length
- 33229
- Individuals with no LoFs
- 125712
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 36
- Defined
- 125748
- p
- 0.000143
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.69 | 141 | 330 | 0.428 | 0.0000173 | 3859 |
| Missense (PolyPhen) | 32 | 134.59 | 0.23776 | 1568 | ||
| Synonymous | 0.395 | 111 | 116 | 0.953 | 0.00000622 | 1118 |
| Loss of Function | 4.85 | 5 | 36.7 | 0.136 | 0.00000185 | 443 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0.00055 | 0.00050 | rare |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0.000092 | 0.000092 | rare |
| European (Non-Finnish) | 0.00022 | 0.00022 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: This enzyme is involved in the de novo synthesis of CTP, a precursor of DNA, RNA and phospholipids. Catalyzes the ATP- dependent amination of UTP to CTP with either L-glutamine or ammonia as a source of nitrogen. This enzyme and its product, CTP, play a crucial role in the proliferation of activated lymphocytes and therefore in immunity. {ECO:0000269|PubMed:16179339, ECO:0000269|PubMed:24870241}.;
- Disease
- DISEASE: Immunodeficiency 24 (IMD24) [MIM:615897]: A life- threatening immunodeficiency, characterized by an impaired capacity of activated T and B cells to proliferate in response to antigen receptor-mediated activation. Patients have early onset of severe chronic viral infections, mostly caused by herpes viruses, including EBV and varicella zooster virus (VZV), and also suffer from recurrent encapsulated bacterial infections, a spectrum of infections typical of a combined deficiency of adaptive immunity. {ECO:0000269|PubMed:24870241}. Note=The disease is caused by mutations affecting the gene represented in this entry. A unique and recessive G to C mutation probably affecting a splice donor site at the junction of intron 17-18 and exon 18 has been identified in all patients. It results in expression of an abnormal transcript lacking exon 18 and a complete loss of the expression of the protein. {ECO:0000269|PubMed:24870241}.;
Recessive Scores
- pRec
- 0.262
Intolerance Scores
- RVIS EVS
- -0.74
- RVIS percentile EVS
- 13.94
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |