GeneBe

ATR

protein-coding

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

Gene summary

The protein encoded by this gene is a serine/threonine kinase and DNA damage sensor, activating cell cycle checkpoint signaling upon DNA stress. The encoded protein can phosphorylate and activate several proteins involved in the inhibition of DNA replication and mitosis, and can promote DNA repair, recombination, and apoptosis. This protein is also important for fragile site stability and centrosome duplication. Defects in this gene are a cause of Seckel syndrome 1. [provided by RefSeq, Aug 2017]

MANE transcript

NM_001184.4

Inheritance

AR, AD

ClinVar variants

P:141U:2199B:1249

Top phenotype

Cutaneous telangiectasia and cancer syndrome, familial; Seckel syndrome 1

gnomAD constraint

pLI —, LoF o/e 0.31

Max pathogenic AF

—

Genomic locus

chr3:142,449,007-142,578,733

External References & Databases

Ensembl (ENSG00000175054)NCBI Gene (545)OMIM (601215)HGNC:882GenCCUniProt (Q13535)AlphaFoldClinVar (ATR)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~129.7 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndromeLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0013806

Submitter: Labcorp Genetics (formerly Invitae)

Seckel syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008869

Submitter: G2P

familial prostate carcinomaLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0023122

Submitter: Ambry Genetics

Seckel syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008869

Submitter: Ambry Genetics

sarcomaMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0005089

Submitter: Genomics England PanelApp

Seckel syndrome 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008869

Submitter: Illumina

familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013806

Submitter: Orphanet

Seckel syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019342

Submitter: Orphanet

Seckel syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008869

Submitter: PanelApp Australia

familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0013806

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Cutaneous telangiectasia and cancer syndrome, familial; Seckel syndrome 1AD/AR

Manifestation: Craniofacial; Dental; Dermatologic; Musculoskeletal; Neurologic; Oncologic

Intervention: Oncologic

Rationale: 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

Refs: 13869653; 6022184; 4378248; 7046443; 8358044; 8182723; 9128935; 10889046; 12640452; 22341969; 23111928; 30199583; 30846821Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ATR variants in ClinVar

15 Conditions Cataloged
Inborn genetic diseasesTotal: 2794
not providedTotal: 2027
Seckel syndrome 1Total: 477
Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndromeTotal: 402
not specifiedTotal: 220
ATR-related disorderTotal: 85
Hereditary cancer-predisposing syndromeTotal: 32
MicrocephalyTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001184.4. 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.

EffectPLPVUSLBBSum
synonymous
23
clinvar
1170
clinvar
7
clinvar
 1200
missense
2
clinvar
1
clinvar
2149
clinvar
67
clinvar
4
clinvar
 2223
nonsense
30
clinvar
12
clinvar
8
clinvar
 50
start loss
2
clinvar
 2
frameshift
54
clinvar
12
clinvar
3
clinvar
 69
splice donor/acceptor (+/-2bp)
2
clinvar
28
clinvar
14
clinvar
1
clinvar
 45
Total885321991238113589

Highest pathogenic variant AF is 0.0009636137

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 27 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001184.4RefSeqNP_001175.247MANE Select
ENST00000350721.9EnsemblENSP00000343741.447MANE Select
NM_001354579.2RefSeqNP_001341508.146Standard
ENST00000507148.1EnsemblENSP00000426595.14Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
atrDanio rerio

Structure: head

Quality: decreased size

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • 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)

Biological Process

  • DNA damage checkpoint
  • telomere maintenance
  • DNA replication
  • DNA repair
  • cellular response to DNA damage stimulus

Molecular Function

  • DNA binding
  • protein kinase activity
  • protein serine/threonine kinase activity
  • protein binding
  • ATP binding

Cellular Component

  • nuclear chromosome, telomeric region
  • nucleus
  • nucleoplasm
  • chromosome
  • Golgi apparatus

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000350721
Coding exons
47
Length
129592
Individuals with no LoFs
125524
Homozygous LoFs
1
Heterozygous LoFs
223
Defined
125748
p
0.000891
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense4.369151.37e+30.6680.000068717423
Missense (PolyPhen)247544.680.453476918
Synonymous0.8044584800.9530.00002394949
Loss of Function7.55431390.3090.000007701713

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000750.00074rare
Latino/Admixed American0.000700.00069rare
Ashkenazi Jewish0.0000990.000099rare
East Asian0.000710.00071rare
Finnish0.000320.00032rare
European (Non-Finnish)0.000460.00045rare
South Asian0.00370.0036notable
Other0.000820.00081rare

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec
0.143

Intolerance Scores

LoFtool
0.718
RVIS EVS
-1.64
RVIS percentile EVS
2.79

Essentials

Essential (CRISPR)
E
Essential (CRISPR2)
E
Essential (gene trap)
E
Indispensability pred.
E
Indispensability score
0.846

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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