ATIC
protein-coding5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase, the group of Purinosome
Gene summary
This gene encodes a bifunctional protein that catalyzes the last two steps of the de novo purine biosynthetic pathway. The N-terminal domain has phosphoribosylaminoimidazolecarboxamide formyltransferase activity, and the C-terminal domain has IMP cyclohydrolase activity. A mutation in this gene results in AICA-ribosiduria. [provided by RefSeq, Sep 2009]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~37.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0012099
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0012099
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0012099
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0012099
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Craniofacial; Dermatologic; Neurologic; Ophthalmologic
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 ATIC variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_004044.7. 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 | 7 | 26 | 1 | 34 | ||
| missense | 3 | 101 | 11 | 5 | 120 | |
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 1 | 4 | 3 | 8 | ||
| splice donor/acceptor (+/-2bp) | 3 | 3 | 6 | |||
| Total | 2 | 10 | 114 | 37 | 6 | 169 |
Highest pathogenic variant AF is 0.00015944966
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_004035.2 | 16 | MANE Select | |
| Ensembl | ENSP00000236959.9 | 16 | MANE Select | |
| Ensembl | ENSP00000402393.1 | 5 | Standard | |
| Ensembl | ENSP00000401936.1 | 5 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Antimetabolite Pathway - Folate Cycle, Pharmacodynamics
- One carbon pool by folate - Homo sapiens (human)
- Purine metabolism - Homo sapiens (human)
- Methotrexate Pathway (Cancer Cell), Pharmacodynamics
- Purine Nucleoside Phosphorylase Deficiency
Biological Process
- brainstem development
- nucleobase-containing compound metabolic process
- 'de novo' IMP biosynthetic process
- nucleoside metabolic process
- purine ribonucleoside monophosphate biosynthetic process
Molecular Function
- IMP cyclohydrolase activity
- phosphoribosylaminoimidazolecarboxamide formyltransferase activity
- protein homodimerization activity
- cadherin binding
Cellular Component
- cytosol
- plasma membrane
- membrane
- extracellular exosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000236959
- Coding exons
- 16
- Length
- 37948
- Individuals with no LoFs
- 125613
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 135
- Defined
- 125748
- p
- 0.000537
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.482 | 352 | 327 | 1.07 | 0.0000179 | 3844 |
| Missense (PolyPhen) | 140 | 141.44 | 0.98979 | 1671 | ||
| Synonymous | -1.30 | 143 | 125 | 1.15 | 0.00000780 | 1169 |
| Loss of Function | 0.421 | 30 | 32.6 | 0.920 | 0.00000170 | 397 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00018 | 0.00018 | rare |
| Latino/Admixed American | 0.00040 | 0.00040 | rare |
| Ashkenazi Jewish | 0.0014 | 0.0014 | notable |
| East Asian | 0.00060 | 0.00060 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00063 | 0.00063 | rare |
| South Asian | 0.00059 | 0.00056 | rare |
| Other | 0.00065 | 0.00065 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Bifunctional enzyme that catalyzes 2 steps in purine biosynthesis. {ECO:0000269|PubMed:14966129}.;
- Disease
- DISEASE: AICAR transformylase/IMP cyclohydrolase deficiency (AICAR) [MIM:608688]: A neurologically devastating inborn error of purine biosynthesis. Patients excrete massive amounts of AICA- riboside in the urine and accumulate AICA-ribotide and its derivatives in erythrocytes and fibroblasts. AICAR causes profound mental retardation, epilepsy, dysmorphic features and congenital blindness. {ECO:0000269|PubMed:15114530}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.700
Intolerance Scores
- LoFtool
- 0.615
- RVIS EVS
- 0.25
- RVIS percentile EVS
- 69.62
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.968
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | High |
| Cancer | Medium | Medium | Medium |