ACO1
protein-codingaconitase 1
Gene summary
The protein encoded by this gene is a bifunctional, cytosolic protein that functions as an essential enzyme in the TCA cycle and interacts with mRNA to control the levels of iron inside cells. When cellular iron levels are high, this protein binds to a 4Fe-4S cluster and functions as an aconitase. Aconitases are iron-sulfur proteins that function to catalyze the conversion of citrate to isocitrate. When cellular iron levels are low, the protein binds to iron-responsive elements (IREs), which are stem-loop structures found in the 5' UTR of ferritin mRNA, and in the 3' UTR of transferrin receptor mRNA. When the protein binds to IRE, it results in repression of translation of ferritin mRNA, and inhibition of degradation of the otherwise rapidly degraded transferrin receptor mRNA. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. Alternative splicing results in multiple transcript variants [provided by RefSeq, Jan 2014]
- IREB1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~70.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
No GenCC data available for this gene.
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ACO1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002197.3. 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 | 1 | 5 | 7 | 13 | ||
| missense | 109 | 6 | 2 | 117 | ||
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 8 | 8 | ||||
| Total | 0 | 0 | 120 | 11 | 9 | 140 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002188.1 | 20 | MANE Select | |
| Ensembl | ENSP00000309477.5 | 20 | MANE Select | |
| RefSeq | NP_001265281.1 | 20 | Standard | |
| RefSeq | NP_001349769.1 | 20 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| aco1 | Danio rerio | Structure: nucleate erythrocyte Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Citrate cycle (TCA cycle) - Homo sapiens (human)
- Doxorubicin Pathway (Cardiomyocyte Cell), Pharmacodynamics
- Glyoxylate and dicarboxylate metabolism - Homo sapiens (human)
- Warburg Effect
- The oncogenic action of Succinate
Biological Process
- tricarboxylic acid cycle
- citrate metabolic process
- regulation of translation
- cellular iron ion homeostasis
- post-embryonic development
Molecular Function
- RNA binding
- aconitate hydratase activity
- protein binding
- iron-responsive element binding
- metal ion binding
Cellular Component
- cytoplasm
- mitochondrion
- endoplasmic reticulum
- Golgi apparatus
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000309951
- Coding exons
- 20
- Length
- 70150
- Individuals with no LoFs
- 125583
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 165
- Defined
- 125748
- p
- 0.000656
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.919 | 454 | 513 | 0.886 | 0.0000282 | 5829 |
| Missense (PolyPhen) | 172 | 220.72 | 0.77927 | 2370 | ||
| Synonymous | -0.131 | 192 | 190 | 1.01 | 0.0000109 | 1741 |
| Loss of Function | 1.94 | 35 | 49.8 | 0.703 | 0.00000300 | 538 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00056 | 0.00055 | rare |
| Latino/Admixed American | 0.00012 | 0.00012 | rare |
| Ashkenazi Jewish | 0.0013 | 0.0013 | notable |
| East Asian | 0.00049 | 0.00049 | rare |
| Finnish | 0.00046 | 0.00046 | rare |
| European (Non-Finnish) | 0.00086 | 0.00086 | rare |
| South Asian | 0.00059 | 0.00059 | rare |
| Other | 0.00067 | 0.00065 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Iron sensor. Binds a 4Fe-4S cluster and functions as aconitase when cellular iron levels are high. Functions as mRNA binding protein that regulates uptake, sequestration and utilization of iron when cellular iron levels are low. Binds to iron-responsive elements (IRES) in target mRNA species when iron levels are low. Binding of a 4Fe-4S cluster precludes RNA binding. {ECO:0000269|PubMed:1946430, ECO:0000269|PubMed:23891004, ECO:0000269|PubMed:8041788}.;
Recessive Scores
- pRec
- 0.612
Intolerance Scores
- LoFtool
- 0.905
- RVIS EVS
- -1.08
- RVIS percentile EVS
- 7.24
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.999
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |