TIMELESS

timeless circadian regulator

Basic information

Region (hg38): 12:56416362-56449426

Links

ENSG00000111602 ∙ NCBI:8914 ∙ OMIM:603887 ∙ HGNC:11813 ∙ Uniprot:Q9UNS1 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

No genCC data.

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Advance sleep phase syndrome, familial, 4	AD	General	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	Neurologic	31138685

ClinVar

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

• Inborn genetic diseases (68 variants)
• not provided (18 variants)
• Advance sleep phase syndrome, familial, 4 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TIMELESS 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				7	1	8
missense			66	5	6	77
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region				1		1
non coding					1	1
Total	0	0	66	12	8

Variants in TIMELESS

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

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

Position	Type	Phenotype	Significance	ClinVar
12-56417765-C-T			Likely benign (Apr 04, 2018)
12-56417778-A-C		not specified	Uncertain significance (Feb 14, 2023)
12-56417963-T-G		not specified	Uncertain significance (Aug 02, 2021)
12-56417984-G-A		not specified	Uncertain significance (Feb 15, 2023)
12-56417988-C-G		not specified	Uncertain significance (Jan 26, 2023)
12-56417999-G-T		not specified	Uncertain significance (Aug 04, 2023)
12-56418000-C-T		not specified	Likely benign (Feb 23, 2023)
12-56418138-T-C			Likely benign (Mar 01, 2023)
12-56418146-C-T		not specified	Uncertain significance (May 16, 2022)
12-56418153-C-T			Benign/Likely benign (Mar 01, 2022)
12-56418191-C-G		not specified	Uncertain significance (Nov 17, 2022)
12-56418195-T-C			Likely benign (Jun 06, 2018)
12-56418199-C-T		not specified	Uncertain significance (Jul 09, 2021)
12-56418209-T-C		not specified	Uncertain significance (Jan 23, 2023)
12-56418264-C-G		not specified	Uncertain significance (Dec 21, 2022)
12-56418326-G-A		not specified	Uncertain significance (Jan 05, 2022)
12-56418347-G-A		Advanced sleep phase syndrome, familial, 4	Pathogenic (Aug 24, 2022)
12-56420619-A-G			Benign (Jul 31, 2018)
12-56420625-C-T		not specified	Uncertain significance (Aug 15, 2023)
12-56420646-T-C		not specified	Uncertain significance (Apr 06, 2022)
12-56420670-G-C		not specified	Uncertain significance (Jun 16, 2023)
12-56420675-G-C		not specified	Uncertain significance (Oct 12, 2021)
12-56420996-T-C		not specified	Uncertain significance (Dec 07, 2023)
12-56421040-C-G		not specified	Uncertain significance (Jan 31, 2024)
12-56421379-C-T		not specified	Uncertain significance (Dec 09, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TIMELESS	protein_coding	protein_coding	ENST00000553532	28	32285

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
9.85e-35	0.00814	125503	1	244	125748	0.000975

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.0656	684	689	0.993	0.0000413	7876
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00154	0.00145
Ashkenazi Jewish	0.000397	0.000397
East Asian	0.00471	0.00250
Finnish	0.000416	0.000416
European (Non-Finnish)	0.000919	0.000897
Middle Eastern	0.00471	0.00250
South Asian	0.00236	0.00160
Other	0.000491	0.000489

dbNSFP

Source: dbNSFP

• 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}.
• Pathway: HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA);DNA Repair;DNA Double-Strand Break Repair;Homology Directed Repair;Circadian rhythm pathway;Processing of DNA double-strand break ends;ATR signaling pathway (Consensus)

Recessive Scores

• pRec: 0.204

Intolerance Scores

• loftool: 0.992
• rvis_EVS: 0.37
• rvis_percentile_EVS: 75.13

Haploinsufficiency Scores

• pHI: 0.324
• hipred: Y
• hipred_score: 0.513
• ghis: 0.620

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.697

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Timeless
• Phenotype: 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)

Gene ontology

• 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;circadian rhythm;detection of abiotic stimulus;lung development;regulation of cell population proliferation;regulation of circadian rhythm;replication fork arrest;cell cycle phase transition;negative regulation of transcription, DNA-templated;replication fork protection;branching morphogenesis of an epithelial tube;cell division;cellular response to hydroxyurea;cellular response to cisplatin;cellular response to bleomycin;positive regulation of double-strand break repair
• Cellular component: nuclear chromatin;nucleus;nucleoplasm;replication fork protection complex
• Molecular function: DNA binding;protein binding;protein homodimerization activity;protein heterodimerization activity