ATR

ATR serine/threonine kinase, the group of Armadillo like helical domain containing

Basic information

Region (hg38): 3:142449006-142578733

Links

ENSG00000175054 ∙ NCBI:545 ∙ OMIM:601215 ∙ HGNC:882 ∙ Uniprot:Q13535 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Seckel syndrome 1 (Strong), mode of inheritance: AR
• sarcoma (Moderate), mode of inheritance: AD
• familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome (Moderate), mode of inheritance: AD
• Seckel syndrome (Supportive), mode of inheritance: AR
• familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome (Supportive), mode of inheritance: AD
• Seckel syndrome 1 (Definitive), mode of inheritance: AR
• familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome (Limited), mode of inheritance: Unknown

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Cutaneous telangiectasia and cancer syndrome, familial; Seckel syndrome 1	AD/AR	Oncologic	Though both Seckel syndrome 1 and Cutaneous telangiectasia and cancer syndrome, familial are potentially recognizable, surveillance and/or awareness of cancer risk may allow early diagnosis and treatment of oncologic manifestations, which may reduce morbidity and mortality	Craniofacial; Dental; Dermatologic; Musculoskeletal; Neurologic; Oncologic	13869653; 6022184; 4378248; 7046443; 8358044; 8182723; 9128935; 10889046; 12640452; 22341969; 23111928; 30199583; 30846821

ClinVar

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

• Inborn genetic diseases (1985 variants)
• not provided (1471 variants)
• Seckel syndrome 1 (432 variants)
• Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome (355 variants)
• not specified (99 variants)
• Seckel syndrome (9 variants)
• ATR-related condition (9 variants)
• Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome;Seckel syndrome 1 (6 variants)
• Hereditary cancer-predisposing syndrome (5 variants)
• Seckel syndrome 1;Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome (5 variants)
• Microcephaly (2 variants)
• Endometrium neoplasm (1 variants)
• ATR-X-related syndrome (1 variants)
• Familial cancer of breast (1 variants)
• See cases (1 variants)
• Malignant tumor of breast (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ATR 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			16	851	7	874
missense	1		1489	25	7	1522
nonsense	21	4	3			28
start loss			1			1
frameshift	33	3	2			38
inframe indel			10			10
splice donor/acceptor (+/-2bp)	2	13	3			18
splice region			47	49	4	100
non coding		1	12	226	71	310
Total	57	21	1536	1102	85

Highest pathogenic variant AF is 0.0000399

Variants in ATR

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

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

Position	Type	Phenotype	Significance	ClinVar
3-142449134-A-G			Benign (Jun 16, 2018)
3-142449327-G-A		Seckel syndrome 1	Uncertain significance (Jan 12, 2018)
3-142449357-A-C		Seckel syndrome 1	Uncertain significance (Jan 13, 2018)
3-142449433-A-G		Inborn genetic diseases	Uncertain significance (Aug 24, 2022)
3-142449438-T-C		Inborn genetic diseases	Likely benign (Oct 15, 2022)
3-142449440-G-C		Inborn genetic diseases	Uncertain significance (Apr 15, 2023)
3-142449442-G-A			Uncertain significance (Jan 02, 2022)
3-142449451-A-G		Inborn genetic diseases	Uncertain significance (Mar 31, 2023)
3-142449452-G-A			Uncertain significance (Nov 27, 2023)
3-142449458-T-A		Inborn genetic diseases	Uncertain significance (Jan 25, 2023)
3-142449462-G-A		Inborn genetic diseases • Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome;Seckel syndrome 1 • Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome • Seckel syndrome 1	Likely benign (Jan 13, 2024)
3-142449464-A-C		Inborn genetic diseases	Uncertain significance (Dec 14, 2023)
3-142449465-T-C		not specified • Inborn genetic diseases • Seckel syndrome 1 • Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome	Likely benign (Dec 13, 2023)
3-142449468-T-A		Inborn genetic diseases	Uncertain significance (Jul 30, 2023)
3-142449470-A-C		Inborn genetic diseases	Uncertain significance (Dec 15, 2021)
3-142449470-A-G		Inborn genetic diseases	Likely benign (Jun 18, 2022)
3-142449471-G-C		Inborn genetic diseases	Uncertain significance (May 05, 2023)
3-142449474-T-C		Inborn genetic diseases	Likely benign (Dec 04, 2020)
3-142449479-C-G		Inborn genetic diseases	Uncertain significance (Jun 10, 2022)
3-142449479-C-T		Inborn genetic diseases	Uncertain significance (May 07, 2022)
3-142449480-A-G		Inborn genetic diseases	Likely benign (Dec 18, 2022)
3-142449489-C-T		not specified • Seckel syndrome 1 • Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome	Benign/Likely benign (Feb 01, 2024)
3-142449500-A-G		Seckel syndrome 1 • Inborn genetic diseases • Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome	Uncertain significance (Feb 01, 2024)
3-142449501-A-G		Seckel syndrome 1 • Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome • Inborn genetic diseases	Likely benign (Feb 08, 2023)
3-142449503-G-A		Inborn genetic diseases	Uncertain significance (Sep 30, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ATR	protein_coding	protein_coding	ENST00000350721	47	129592

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
3.52e-9	1.00	125524	1	223	125748	0.000891

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	4.36	915	1.37e+3	0.668	0.0000687	17423
Missense in Polyphen		247	544.68	0.45347		6918
Synonymous	0.804	458	480	0.953	0.0000239	4949
Loss of Function	7.55	43	139	0.309	0.00000770	1713

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00145	0.00143
Ashkenazi Jewish	0.0000993	0.0000992
East Asian	0.000707	0.000707
Finnish	0.000324	0.000323
European (Non-Finnish)	0.000459	0.000448
Middle Eastern	0.000707	0.000707
South Asian	0.00367	0.00363
Other	0.000816	0.000815

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Serine/threonine protein kinase which activates checkpoint signaling upon genotoxic stresses such as ionizing radiation (IR), ultraviolet light (UV), or DNA replication stalling, thereby acting as a DNA damage sensor. Recognizes the substrate consensus sequence [ST]-Q. Phosphorylates BRCA1, CHEK1, MCM2, RAD17, RPA2, SMC1 and p53/TP53, which collectively inhibit DNA replication and mitosis and promote DNA repair, recombination and apoptosis. Phosphorylates 'Ser-139' of histone variant H2AX/H2AFX at sites of DNA damage, thereby regulating DNA damage response mechanism. Required for FANCD2 ubiquitination. Critical for maintenance of fragile site stability and efficient regulation of centrosome duplication. {ECO:0000269|PubMed:10597277, ECO:0000269|PubMed:10608806, ECO:0000269|PubMed:10859164, ECO:0000269|PubMed:11114888, ECO:0000269|PubMed:11418864, ECO:0000269|PubMed:11673449, ECO:0000269|PubMed:11721054, ECO:0000269|PubMed:11865061, ECO:0000269|PubMed:12526805, ECO:0000269|PubMed:12791985, ECO:0000269|PubMed:12814551, ECO:0000269|PubMed:14657349, ECO:0000269|PubMed:14729973, ECO:0000269|PubMed:14742437, ECO:0000269|PubMed:15210935, ECO:0000269|PubMed:15314022, ECO:0000269|PubMed:15496423, ECO:0000269|PubMed:16260606, ECO:0000269|PubMed:21144835, ECO:0000269|PubMed:27723717, ECO:0000269|PubMed:27723720, ECO:0000269|PubMed:9427750, ECO:0000269|PubMed:9636169, ECO:0000269|PubMed:9925639}.
• Disease: DISEASE: Seckel syndrome 1 (SCKL1) [MIM:210600]: A rare autosomal recessive disorder characterized by proportionate dwarfism of prenatal onset associated with low birth weight, growth retardation, severe microcephaly with a bird-headed like appearance, and mental retardation. {ECO:0000269|PubMed:12640452}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cutaneous telangiectasia and cancer syndrome, familial (FCTCS) [MIM:614564]: A disease characterized by cutaneous telangiectases in infancy with patchy alopecia over areas of affected skin, thinning of the lateral eyebrows, and mild dental and nail anomalies. Affected individuals are at increased risk of developing oropharyngeal cancer, and other malignancies have been reported as well. {ECO:0000269|PubMed:22341969}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Fanconi anemia pathway - Homo sapiens (human);Cell cycle - Homo sapiens (human);p53 signaling pathway - Homo sapiens (human);HTLV-I infection - Homo sapiens (human);Cellular senescence - Homo sapiens (human);Human papillomavirus infection - Homo sapiens (human);Cell Cycle;miRNA Regulation of DNA Damage Response;TP53 Regulates Transcription of DNA Repair Genes;ATR Signaling;ATM Signaling Network in Development and Disease;DNA Damage Response;HDR through Single Strand Annealing (SSA);HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA);Fanconi Anemia Pathway;DNA Repair;Gene expression (Transcription);DNA Double-Strand Break Repair;role of brca1 brca2 and atr in cancer susceptibility;cell cycle: g1/s check point;regulation of cell cycle progression by plk3;Generic Transcription Pathway;Regulation of HSF1-mediated heat shock response;Homology Directed Repair;Cellular responses to stress;Reproduction;RNA Polymerase II Transcription;G2/M DNA damage checkpoint;Activation of ATR in response to replication stress;G2/M Checkpoints;Cell Cycle Checkpoints;Meiotic synapsis;Meiosis;cell cycle: g2/m checkpoint;Cellular responses to external stimuli;atm signaling pathway;TP53 Regulates Transcription of DNA Repair Genes;Fanconi anemia pathway;Cellular response to heat stress;Regulation of TP53 Activity through Phosphorylation;Regulation of TP53 Activity;Transcriptional Regulation by TP53;Cell Cycle;Circadian rhythm pathway;BARD1 signaling events;Processing of DNA double-strand break ends;ATR signaling pathway;p53 pathway;Presynaptic phase of homologous DNA pairing and strand exchange;Homologous DNA Pairing and Strand Exchange;HDR through Homologous Recombination (HRR) (Consensus)

Recessive Scores

• pRec: 0.143

Intolerance Scores

• loftool: 0.718
• rvis_EVS: -1.64
• rvis_percentile_EVS: 2.79

Haploinsufficiency Scores

• pHI: 0.813
• hipred: Y
• hipred_score: 0.719
• ghis: 0.617

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.846

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Atr
• Phenotype: pigmentation phenotype; neoplasm; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; reproductive system 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); normal phenotype; respiratory system phenotype; liver/biliary system phenotype; embryo phenotype; skeleton phenotype; renal/urinary system phenotype; immune system phenotype; digestive/alimentary phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); endocrine/exocrine gland phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); homeostasis/metabolism phenotype; cellular phenotype; craniofacial phenotype

Zebrafish Information Network

• Gene name: atr
• Affected structure: head
• Phenotype tag: abnormal
• Phenotype quality: decreased size

Gene ontology

• Biological process: DNA damage checkpoint;telomere maintenance;DNA replication;DNA repair;cellular response to DNA damage stimulus;multicellular organism development;negative regulation of DNA replication;peptidyl-serine phosphorylation;positive regulation of telomere maintenance via telomerase;cellular response to UV;interstrand cross-link repair;response to drug;positive regulation of DNA damage response, signal transduction by p53 class mediator;protein autophosphorylation;protein localization to chromosome, telomeric region;cellular response to gamma radiation;replicative senescence;establishment of RNA localization to telomere;establishment of protein-containing complex localization to telomere;regulation of cellular response to heat;positive regulation of telomerase catalytic core complex assembly
• Cellular component: nuclear chromosome, telomeric region;nucleus;nucleoplasm;chromosome;Golgi apparatus;PML body
• Molecular function: DNA binding;protein kinase activity;protein serine/threonine kinase activity;protein binding;ATP binding;MutLalpha complex binding;MutSalpha complex binding