TYMS
protein-codingthymidylate synthetase
Gene summary
Thymidylate synthase catalyzes the methylation of deoxyuridylate to deoxythymidylate using, 10-methylenetetrahydrofolate (methylene-THF) as a cofactor. This function maintains the dTMP (thymidine-5-prime monophosphate) pool critical for DNA replication and repair. The enzyme has been of interest as a target for cancer chemotherapeutic agents. It is considered to be the primary site of action for 5-fluorouracil, 5-fluoro-2-prime-deoxyuridine, and some folate analogs. Expression of this gene and that of a naturally occurring antisense transcript, mitochondrial enolase superfamily member 1 (GeneID:55556), vary inversely when cell-growth progresses from late-log to plateau phase. Polymorphisms in this gene may be associated with etiology of neoplasia, including breast cancer, and response to chemotherapy. [provided by RefSeq, Aug 2017]
- TS
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~15.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
No GenCC data available for this gene.
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Craniofacial; Dental; Dermatologic; Oncologic
Intervention: Allergy/Immunology/Infectious; Oncologic
Rationale: Surveillance (eg, with regularly performed CBC as well as other measures in the presence of concern for hematologic sequelae) for bone marrow failure, as well as surveillance for multiple cancer types (eg, with self-examination and clinical examination) may allow early detection and treatment; Awareness of infectious risk may allow prompt diagnosis and treatment of infections
Comments: Inheritance involves variants in TYMS as well a a specific haplotype in the ENOSF1 gene
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to TYMS variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001071.4. 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 | 1 | 5 | 1 | 7 | ||
| missense | 14 | 4 | 18 | |||
| nonsense | 2 | 1 | 3 | |||
| start loss | 0 | |||||
| frameshift | 2 | 2 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 2 | 3 | |||
| Total | 5 | 0 | 18 | 9 | 1 | 33 |
Highest pathogenic variant AF is 0.0000061574838
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001062.1 | 7 | MANE Select | |
| Ensembl | ENSP00000315644.10 | 7 | MANE Select | |
| RefSeq | NP_001341796.1 | 6 | Standard | |
| RefSeq | NP_001341797.1 | 5 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| tyms | Danio rerio | Structure: melanocyte Quality: quality abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Fluoropyrimidine Pathway, Pharmacodynamics
- Antimetabolite Pathway - Folate Cycle, Pharmacodynamics
- Pyrimidine metabolism - Homo sapiens (human)
- One carbon pool by folate - Homo sapiens (human)
- Fluoropyrimidine Pathway, Pharmacokinetics
Biological Process
- regulation of transcription involved in G1/S transition of mitotic cell cycle
- dTMP biosynthetic process
- dTTP biosynthetic process
- aging
- circadian rhythm
Molecular Function
- nucleotide binding
- translation repressor activity, mRNA regulatory element binding
- thymidylate synthase activity
- folic acid binding
- protein homodimerization activity
Cellular Component
- nucleus
- nucleolus
- cytoplasm
- mitochondrion
- mitochondrial inner membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000323274
- Coding exons
- 7
- Length
- 15975
- Individuals with no LoFs
- 125735
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 5
- Defined
- 125740
- p
- 0.0000199
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.58 | 71 | 164 | 0.433 | 0.00000846 | 2018 |
| Missense (PolyPhen) | 16 | 74.591 | 0.2145 | 886 | ||
| Synonymous | 0.366 | 63 | 66.8 | 0.943 | 0.00000398 | 611 |
| Loss of Function | 3.19 | 3 | 17.3 | 0.173 | 9.74e-7 | 184 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.000018 | 0.000018 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. {ECO:0000269|PubMed:21876188}.;
Recessive Scores
- pRec
- 0.618
Intolerance Scores
- LoFtool
- 0.173
- RVIS EVS
- -0.16
- RVIS percentile EVS
- 41.25
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- S
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.763
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |