ACE
protein-codingangiotensin I converting enzyme, the group of CD molecules
Gene summary
This gene encodes an enzyme involved in blood pressure regulation and electrolyte balance. It catalyzes the conversion of angiotensin I into a physiologically active peptide angiotensin II. Angiotensin II is a potent vasopressor and aldosterone-stimulating peptide that controls blood pressure and fluid-electrolyte balance. This angiotensin converting enzyme (ACE) also inactivates the vasodilator protein, bradykinin. Accordingly, the encoded enzyme increases blood pressure and is a drug target of ACE inhibitors, which are often prescribed to reduce blood pressure. This enzyme additionally plays a role in fertility through its ability to cleave and release GPI-anchored membrane proteins in spermatozoa. Many studies have associated the presence or absence of a 287 bp Alu repeat element in this gene with the levels of circulating enzyme. This polymorphism, as well as mutations in this gene, have been implicated in a wide variety of diseases including cardiovascular pathophysiologies, psoriasis, renal disease, stroke, and Alzheimer's disease. Regulation of the homologous ACE2 gene may be involved in progression of disease caused by several human coronaviruses, including SARS-CoV and SARS-CoV-2. Alternative splicing results in multiple transcript variants encoding both somatic (sACE) and male-specific testicular (tACE) isoforms. [provided by RefSeq, Sep 2020]
- DCP1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~21.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009970
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0009970
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009970
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0700337
Submitter: ClinGen
Angiotensin I-Converting Enzyme (ACE; MIM#106180) catalyzes the conversion of angiotensin I into physiologically active peptide angiotensin II, within the angiotensin-renin system. Biallelic variants in ACE are associated with Renal tubular dysgenesis (AR; MIM#267430). While ACE-associated disorders often lead to pre- peri- or neonatal mortality, there are individuals who survive the infantile period with biallelic ACE variants. The Prenatal Gene Curation Expert Panel has curated ACE with the disease association Renal tubular dysgenesis-ACE. Other variants in ACE, particularly a common 287bp Alu insertion/deletion polymorphism within intron 16 (D and I alleles) are also present in OMIM as susceptibility loci for a variety of conditions, however these entities are outside of the scope of the Prenatal Gene Curation Expert Panel and are not addressed here. The first reported individuals with molecularly confirmed Renal tubular dysgenesis-ACE were reported in Gribouval, et.al 2005 [PMID:16116425], and since it’s initial report, many nonsense, frameshift, canonical splice, missense, and single and/or multi-exon deletions have been reported in affected individuals [PMIDs:16116425, 21695262, 26069751, 30071301, 35286024, 22095942, 33163725]. The molecular mechanism of disease is loss-of-function. Maximum points for genetic evidence was reached in individuals and families with prenatal phenotypes including oligo- or anhydramnios, contractures, increased renal echogenicity, skull ossification defects, intrauterine fetal demise or stillbirth; and neonatal phenotypes including pulmonary hypoplasia and respiratory distress / insufficiency, anuria, severe hypotension, increased susceptibility to gastrointestinal perforations, renal ultrasound anomalies including poor corticomedullary differentiation, non-cystic renal parenchymal disease, loss of corticomedullary demarcation with hypoplastic pelvicalyceal systems and ureters, and neonatal demise [PMIDs:16116425, 21695262, 26069751, 30071301, 35286024, 22095942, 33163725, 35848000, 32198635]. Protein expression, biochemical / enzyme function, and non-human model organisms support the role of ACE in the angiotensin-renin system to catalyze the conversion of angiotensin I to angiotensin II and ACE deficiency leading to renal phenotypes similar to those observed in affected individuals in the literature [PMID:8388857, 13295487, 6270633, 8642790, 9153279, 8598926]. In summary the Prenatal Gene Curation Expert Panel has found sufficient genetic and functional evidence to classify ACE as DEFINITIVE (Gene-Disease Validity SOPv11) for Renal tubular dysgenesis-ACE.
Inheritance Pattern: AR
Disease ID:MONDO:0009970
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0009970
Submitter: PanelApp Australia
Inheritance Pattern: Unknown
Disease ID:MONDO:0013792
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Endocrine; Renal
Intervention: Endocrine; Renal
Rationale: Individuals have been described with severe, early-onset renal and related sequelae, and vasopressin has been described as successfully treating refractory hypotension and anuria; Treatment of low aldosterone (with fludrocortisone) has been described as beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ACE variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000789.4. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 24 | 151 | 8 | 183 | ||
| missense | 1 | 7 | 349 | 42 | 7 | 406 |
| nonsense | 12 | 9 | 2 | 23 | ||
| start loss | 3 | 1 | 4 | |||
| frameshift | 13 | 13 | 3 | 29 | ||
| splice donor/acceptor (+/-2bp) | 2 | 8 | 5 | 15 | ||
| Total | 28 | 40 | 384 | 193 | 15 | 660 |
Highest pathogenic variant AF is 0.0002476551
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000780.1 | 25 | MANE Select | |
| Ensembl | ENSP00000290866.4 | 25 | MANE Select | |
| RefSeq | NP_001171528.1 | 13 | Standard | |
| RefSeq | NP_001369629.1 | 22 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Agents Acting on the Renin-Angiotensin System Pathway, Pharmacodynamics
- Renin-angiotensin system - Homo sapiens (human)
- Hypertrophic cardiomyopathy (HCM) - Homo sapiens (human)
- Chagas disease (American trypanosomiasis) - Homo sapiens (human)
- Renin secretion - Homo sapiens (human)
Biological Process
- kidney development
- blood vessel remodeling
- angiotensin maturation
- regulation of renal output by angiotensin
- neutrophil mediated immunity
Molecular Function
- endopeptidase activity
- carboxypeptidase activity
- drug binding
- metallopeptidase activity
- exopeptidase activity
Cellular Component
- extracellular region
- extracellular space
- lysosome
- endosome
- plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000290866
- Coding exons
- 25
- Length
- 44784
- Individuals with no LoFs
- 125471
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 277
- Defined
- 125748
- p
- 0.00110
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.693 | 797 | 744 | 1.07 | 0.0000490 | 8524 |
| Missense (PolyPhen) | 312 | 300.94 | 1.0368 | 3489 | ||
| Synonymous | -3.33 | 399 | 323 | 1.24 | 0.0000231 | 2494 |
| Loss of Function | 0.978 | 62 | 70.9 | 0.875 | 0.00000368 | 735 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00074 | 0.00074 | rare |
| Latino/Admixed American | 0.0012 | 0.0012 | notable |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00087 | 0.00087 | rare |
| Finnish | 0.0029 | 0.0028 | notable |
| European (Non-Finnish) | 0.0010 | 0.0010 | notable |
| South Asian | 0.00079 | 0.00078 | rare |
| Other | 0.0015 | 0.0015 | notable |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Converts angiotensin I to angiotensin II by release of the terminal His-Leu, this results in an increase of the vasoconstrictor activity of angiotensin. Also able to inactivate bradykinin, a potent vasodilator. Has also a glycosidase activity which releases GPI-anchored proteins from the membrane by cleaving the mannose linkage in the GPI moiety.;
- Disease
- DISEASE: Ischemic stroke (ISCHSTR) [MIM:601367]: A stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. Ischemic strokes, resulting from vascular occlusion, is considered to be a highly complex disease consisting of a group of heterogeneous disorders with multiple genetic and environmental risk factors. {ECO:0000269|PubMed:15534175}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Renal tubular dysgenesis (RTD) [MIM:267430]: Autosomal recessive severe disorder of renal tubular development characterized by persistent fetal anuria and perinatal death, probably due to pulmonary hypoplasia from early-onset oligohydramnios (the Potter phenotype). {ECO:0000269|PubMed:16116425}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Microvascular complications of diabetes 3 (MVCD3) [MIM:612624]: Pathological conditions that develop in numerous tissues and organs as a consequence of diabetes mellitus. They include diabetic retinopathy, diabetic nephropathy leading to end- stage renal disease, and diabetic neuropathy. Diabetic retinopathy remains the major cause of new-onset blindness among diabetic adults. It is characterized by vascular permeability and increased tissue ischemia and angiogenesis. {ECO:0000269|PubMed:10099885}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Intracerebral hemorrhage (ICH) [MIM:614519]: A pathological condition characterized by bleeding into one or both cerebral hemispheres including the basal ganglia and the cerebral cortex. It is often associated with hypertension and craniocerebral trauma. Intracerebral bleeding is a common cause of stroke. {ECO:0000269|PubMed:15277638}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.719
Intolerance Scores
- LoFtool
- 0.822
- RVIS EVS
- -0.57
- RVIS percentile EVS
- 18.91
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.725
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |