AXIN1
protein-codingaxin 1, the group of Protein phosphatase 1 regulatory subunits
Gene summary
This gene encodes a cytoplasmic protein which contains a regulation of G-protein signaling (RGS) domain and a dishevelled and axin (DIX) domain. The encoded protein interacts with adenomatosis polyposis coli, catenin beta-1, glycogen synthase kinase 3 beta, protein phosphate 2, and itself. This protein functions as a negative regulator of the wingless-type MMTV integration site family, member 1 (WNT) signaling pathway and can induce apoptosis. The crystal structure of a portion of this protein, alone and in a complex with other proteins, has been resolved. Mutations in this gene have been associated with hepatocellular carcinoma, hepatoblastomas, ovarian endometriod adenocarcinomas, and medullablastomas. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~65.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0005484
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0011928
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0957832
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Cardiovascular; Gastrointestinal; Genitourinary; Hematologic; Musculoskeletal; Neurologic
Intervention: Allergy/Immunology/Infectious; Cardiovascular
Rationale: Individuals may have pancytopenia and susceptibility to infections, and antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial;Among other features, the condition may include cardiovascular anomalies, and awareness may allow early identification and management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to AXIN1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_003502.4. 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 | 1 | 34 | 7 | 42 | ||
| missense | 110 | 12 | 3 | 125 | ||
| nonsense | 2 | 3 | 5 | |||
| start loss | 0 | |||||
| frameshift | 2 | 2 | ||||
| splice donor/acceptor (+/-2bp) | 8 | 8 | ||||
| Total | 4 | 0 | 122 | 46 | 10 | 182 |
Highest pathogenic variant AF is 0.000007716255
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_003493.1 | 10 | MANE Select | |
| Ensembl | ENSP00000262320.3 | 10 | MANE Select | |
| RefSeq | NP_851393.1 | 9 | Standard | |
| Ensembl | ENSP00000346935.3 | 9 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| axin1 | Danio rerio | Structure: intestinal epithelial cell Quality: proliferative abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Gastric cancer - Homo sapiens (human)
- Cushing,s syndrome - Homo sapiens (human)
- Breast cancer - Homo sapiens (human)
- Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human)
- Basal cell carcinoma - Homo sapiens (human)
Biological Process
- positive regulation of protein phosphorylation
- apoptotic process
- multicellular organism development
- positive regulation of peptidyl-threonine phosphorylation
- Wnt signaling pathway
Molecular Function
- protein binding
- beta-catenin binding
- enzyme binding
- protein kinase binding
- receptor signaling complex scaffold activity
Cellular Component
- nucleus
- cytoplasm
- cytosol
- lateral plasma membrane
- beta-catenin destruction complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000262320
- Coding exons
- 10
- Length
- 65234
- Individuals with no LoFs
- 125732
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 8
- Defined
- 125740
- p
- 0.0000318
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.01 | 481 | 548 | 0.878 | 0.0000382 | 5552 |
| Missense (PolyPhen) | 145 | 201.7 | 0.71888 | 2079 | ||
| Synonymous | -2.24 | 289 | 244 | 1.18 | 0.0000195 | 1745 |
| Loss of Function | 4.31 | 8 | 35.8 | 0.223 | 0.00000215 | 385 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000039 | 0.000035 | rare |
| South Asian | 0.000066 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Component of the beta-catenin destruction complex required for regulating CTNNB1 levels through phosphorylation and ubiquitination, and modulating Wnt-signaling (PubMed:12192039, PubMed:27098453). Controls dorsoventral patterning via two opposing effects; down-regulates CTNNB1 to inhibit the Wnt signaling pathway and ventralize embryos, but also dorsalizes embryos by activating a Wnt-independent JNK signaling pathway (PubMed:12192039). In Wnt signaling, probably facilitates the phosphorylation of CTNNB1 and APC by GSK3B (PubMed:12192039). Likely to function as a tumor suppressor. Enhances TGF-beta signaling by recruiting the RNF111 E3 ubiquitin ligase and promoting the degradation of inhibitory SMAD7 (PubMed:16601693). Also component of the AXIN1-HIPK2-TP53 complex which controls cell growth, apoptosis and development (PubMed:17210684). Facilitates the phosphorylation of TP53 by HIPK2 upon ultraviolet irradiation (PubMed:17210684). {ECO:0000269|PubMed:12192039, ECO:0000269|PubMed:16601693, ECO:0000269|PubMed:17210684, ECO:0000269|PubMed:27098453}.;
- Disease
- DISEASE: Hepatocellular carcinoma (HCC) [MIM:114550]: A primary malignant neoplasm of epithelial liver cells. The major risk factors for HCC are chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, prolonged dietary aflatoxin exposure, alcoholic cirrhosis, and cirrhosis due to other causes. {ECO:0000269|PubMed:12101426}. Note=The gene represented in this entry is involved in disease pathogenesis.; DISEASE: Caudal duplication anomaly (CADUA) [MIM:607864]: A condition characterized by the occurrence of duplications of different organs in the caudal region. {ECO:0000269|PubMed:16773576}. Note=The disease is caused by mutations affecting the gene represented in this entry. Caudal duplication anomaly is associated with hypermethylation of the AXIN1 promoter.;
Recessive Scores
- pRec
- 0.0978
Intolerance Scores
- LoFtool
- 0.169
- RVIS EVS
- -1.43
- RVIS percentile EVS
- 4.02
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.996
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |