TIMELESS
protein-codingtimeless circadian regulator
Gene summary
The protein encoded by this gene is highly conserved and is involved in cell survival after damage or stress, increase in DNA polymerase epsilon activity, maintenance of telomere length, and epithelial cell morphogenesis. The encoded protein also plays a role in the circadian rhythm autoregulatory loop, interacting with the PERIOD genes (PER1, PER2, and PER3) and others to downregulate activation of PER1 by CLOCK/ARNTL. Changes in this gene or its expression may promote prostate cancer, lung cancer, breast cancer, and mental disorders. [provided by RefSeq, Feb 2014]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~33.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
No GenCC data available for this gene.
Clinical Genomic Database (CGD)
Manifestation: Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to TIMELESS variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_003920.5. 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 | 2 | 13 | 1 | 16 | ||
| missense | 185 | 11 | 3 | 199 | ||
| nonsense | 1 | 1 | 2 | |||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 9 | 9 | ||||
| Total | 1 | 0 | 197 | 24 | 4 | 226 |
Highest pathogenic variant AF is 0.000010569418
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_003911.2 | 28 | MANE Select | |
| Ensembl | ENSP00000450607.1 | 28 | MANE Select | |
| RefSeq | NP_001317224.1 | 28 | Standard | |
| Ensembl | ENSP00000229201.4 | 28 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA)
- DNA Repair
- DNA Double-Strand Break Repair
- Homology Directed Repair
- Circadian rhythm pathway
Biological Process
- DNA replication checkpoint
- negative regulation of transcription by RNA polymerase II
- morphogenesis of an epithelium
- DNA repair
- cellular response to DNA damage stimulus
Molecular Function
- DNA binding
- protein binding
- protein homodimerization activity
- protein heterodimerization activity
Cellular Component
- nuclear chromatin
- nucleus
- nucleoplasm
- replication fork protection complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000553532
- Coding exons
- 28
- Length
- 32285
- Individuals with no LoFs
- 125503
- Homozygous LoFs
- 1
- Heterozygous LoFs
- 244
- Defined
- 125748
- p
- 0.000975
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.0656 | 684 | 689 | 0.993 | 0.0000413 | 7876 |
| Missense (PolyPhen) | 169 | 178.94 | 0.94445 | 2004 | ||
| Synonymous | -0.379 | 267 | 259 | 1.03 | 0.0000136 | 2350 |
| Loss of Function | 1.72 | 62 | 78.4 | 0.791 | 0.00000501 | 775 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.0011 | 0.00098 | notable |
| Latino/Admixed American | 0.00046 | 0.00046 | rare |
| Ashkenazi Jewish | 0.00040 | 0.00040 | rare |
| East Asian | 0.0047 | 0.0025 | notable |
| Finnish | 0.00042 | 0.00042 | rare |
| European (Non-Finnish) | 0.00092 | 0.00090 | rare |
| South Asian | 0.0024 | 0.0016 | notable |
| Other | 0.00049 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Plays an important role in the control of DNA replication, maintenance of replication fork stability, maintenance of genome stability throughout normal DNA replication and in the regulation of the circadian clock. Involved in the determination of period length and in the DNA damage-dependent phase advancing of the circadian clock. Negatively regulates CLOCK|NPAS2-ARTNL/BMAL1|ARTNL2/BMAL2-induced transactivation of PER1 possibly via translocation of PER1 into the nucleus. Forms a complex with TIPIN and this complex regulates DNA replication processes under both normal and stress conditions, stabilizes replication forks and influences both CHEK1 phosphorylation and the intra-S phase checkpoint in response to genotoxic stress. Timeless promotes TIPIN nuclear localization. Involved in cell survival after DNA damage or replication stress. May be specifically required for the ATR-CHEK1 pathway in the replication checkpoint induced by hydroxyurea or ultraviolet light. May also play an important role in epithelial cell morphogenesis and formation of branching tubules. {ECO:0000269|PubMed:17141802, ECO:0000269|PubMed:17296725, ECO:0000269|PubMed:23418588, ECO:0000269|PubMed:9856465}.;
Recessive Scores
- pRec
- 0.204
Intolerance Scores
- LoFtool
- 0.992
- RVIS EVS
- 0.37
- RVIS percentile EVS
- 75.13
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.697
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | High | High | High |
| Primary Immunodeficiency | High | High | High |
| Cancer | High | High | High |