A2M
protein-codingalpha-2-macroglobulin, the group of Alpha-2-macroglobulin family
Gene summary
The protein encoded by this gene is a protease inhibitor and cytokine transporter. It uses a bait-and-trap mechanism to inhibit a broad spectrum of proteases, including trypsin, thrombin and collagenase. It can also inhibit inflammatory cytokines, and it thus disrupts inflammatory cascades. Mutations in this gene are a cause of alpha-2-macroglobulin deficiency. This gene is implicated in Alzheimer's disease (AD) due to its ability to mediate the clearance and degradation of A-beta, the major component of beta-amyloid deposits. A related pseudogene, which is also located on the p arm of chromosome 12, has been identified. [provided by RefSeq, Nov 2016]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~48.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: Unknown
Disease ID:MONDO:0007088
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: General
Intervention: General
Rationale: The clinical consequences of variants are unclear
Comments: Variants have been implicated in pulmonary disease, but the evidence appears mixed
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to A2M variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000014.6. 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 | 3 | 21 | 5 | 29 | ||
| missense | 152 | 14 | 5 | 171 | ||
| nonsense | 4 | 4 | ||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 13 | 1 | 14 | |||
| Total | 0 | 0 | 172 | 35 | 11 | 218 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000005.3 | 36 | MANE Select | |
| Ensembl | ENSP00000323929.8 | 36 | MANE Select | |
| RefSeq | NP_001334352.2 | 36 | Standard | |
| RefSeq | NP_001334353.2 | 34 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Complement and coagulation cascades - Homo sapiens (human)
- Human Complement System
- Dengue-2 Interactions with Complement and Coagulation Cascades
- Complement and Coagulation Cascades
- Signal Transduction
Biological Process
- negative regulation of complement activation, lectin pathway
- platelet degranulation
- blood coagulation, intrinsic pathway
- negative regulation of endopeptidase activity
- extracellular matrix disassembly
Molecular Function
- protease binding
- serine-type endopeptidase inhibitor activity
- GTPase activator activity
- signaling receptor binding
- protein binding
Cellular Component
- extracellular region
- cytosol
- platelet alpha granule lumen
- collagen-containing extracellular matrix
- extracellular exosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000318602
- Coding exons
- 36
- Length
- 48566
- Individuals with no LoFs
- 125656
- Homozygous LoFs
- 1
- Heterozygous LoFs
- 91
- Defined
- 125748
- p
- 0.000366
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.87 | 627 | 773 | 0.811 | 0.0000404 | 9524 |
| Missense (PolyPhen) | 109 | 167.8 | 0.6496 | 2089 | ||
| Synonymous | 1.65 | 269 | 306 | 0.880 | 0.0000170 | 2896 |
| Loss of Function | 4.90 | 32 | 79.0 | 0.405 | 0.00000403 | 963 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00064 | 0.00062 | rare |
| Latino/Admixed American | 0.00047 | 0.00046 | rare |
| Ashkenazi Jewish | 0.00011 | 0.000099 | rare |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0.000093 | 0.000092 | rare |
| European (Non-Finnish) | 0.00048 | 0.00046 | rare |
| South Asian | 0.00030 | 0.00029 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Is able to inhibit all four classes of proteinases by a unique 'trapping' mechanism. This protein has a peptide stretch, called the 'bait region' which contains specific cleavage sites for different proteinases. When a proteinase cleaves the bait region, a conformational change is induced in the protein which traps the proteinase. The entrapped enzyme remains active against low molecular weight substrates (activity against high molecular weight substrates is greatly reduced). Following cleavage in the bait region, a thioester bond is hydrolyzed and mediates the covalent binding of the protein to the proteinase.;
Recessive Scores
- pRec
- 0.796
Intolerance Scores
- LoFtool
- 0.944
- RVIS EVS
- 0.1
- RVIS percentile EVS
- 60.76
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.930
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |