AMER1
protein-codingAPC membrane recruitment protein 1, the group of APC membrane recruitment proteins
Gene summary
The protein encoded by this gene upregulates trancriptional activation by the Wilms tumor protein and interacts with many other proteins, including CTNNB1, APC, AXIN1, and AXIN2. Defects in this gene are a cause of osteopathia striata with cranial sclerosis (OSCS). [provided by RefSeq, May 2010]
- FAM123B
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~20.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: XL
Disease ID:MONDO:0010310
Submitter: Genomics England PanelApp
Inheritance Pattern: XL
Disease ID:MONDO:0010310
Submitter: PanelApp Australia
Inheritance Pattern: XL
Disease ID:MONDO:0010310
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010310
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: XL
Disease ID:MONDO:0010310
Submitter: ClinGen
APC Membrane Recruitment Protein 1 (AMER1; MIM#300647) is an inhibitor of the canonical WNT signaling pathway and is involved in ubiquitination and degradation of beta-catenin. AMER1, also called WTX, is a X-linked gene associated with Osteopathia striata with cranial sclerosis (OSCS, XL; MIM#300373). The molecular etiology of OSCS was first described by Jenkins, et.al in 2008 [PMID:19079258] and has been described in many affected male and female individuals since [PMID:20209645, 20950377, 25296999, 28425981, 34622833, 34414661, others]. Variants are nonsense, frameshift, and small inter- or intragenic deletions, and LOF is the proposed mechanism of disease. Phenotypes in females are variable though often include cranial sclerosis and metaphyseal striations of the long bones. Phenotypes in males are also variable and can be associated with mild phenotypes similar to those seen in females or in more severe cases, with multiple congenital anomalies resulting in demise in utero or in the neonatal or early infantile period. Genetic evidence for AMER1 and Osteopathia striata with cranial sclerosis was scored at the maximum of 12 points and includes both male and female probands with some variants segregating in affected families. Functional evidence including expression studies [PMID:19079258] and mouse models recapitulating the observed human phenotype [PMID:29329488, 21571217] were scored for an additional 2.5 points. Given this and its replication in the literature over time, the association with the AMER1 gene and Osteopathia striata with cranial sclerosis is curated as Definitive by the Prenatal Gene Curation Expert Panel.
Inheritance Pattern: XL
Disease ID:MONDO:0010310
Submitter: G2P
Inheritance Pattern: XL
Disease ID:MONDO:0010310
Submitter: Illumina
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic; Cardiovascular; Craniofacial; Gastrointestinal; Genitourinary; Musculoskeletal; Neurologic
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 AMER1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_152424.4. 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 | 8 | 113 | 17 | 138 | ||
| missense | 320 | 99 | 33 | 452 | ||
| nonsense | 13 | 9 | 15 | 37 | ||
| start loss | 1 | 1 | ||||
| frameshift | 19 | 11 | 9 | 39 | ||
| splice donor/acceptor (+/-2bp) | 2 | 2 | ||||
| Total | 34 | 20 | 352 | 212 | 51 | 669 |
Highest pathogenic variant AF is 9.258368e-7
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_689637.3 | 1 | MANE Select | |
| Ensembl | ENSP00000364003.4 | 1 | MANE Select |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| amer1 | Danio rerio | Structure: head Quality: malformed abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Degradation of beta-catenin by the destruction complex
- Degradation of beta-catenin by the destruction complex
- Signaling by WNT
- Signal Transduction
- Disassembly of the destruction complex and recruitment of AXIN to the membrane
Biological Process
- Wnt signaling pathway
- positive regulation of protein ubiquitination
- bone development
- adipose tissue development
- regulation of canonical Wnt signaling pathway
Molecular Function
- protein binding
- phosphatidylinositol-4,5-bisphosphate binding
- beta-catenin binding
- beta-catenin destruction complex binding
Cellular Component
- cytosol
- plasma membrane
- nuclear body
- intracellular membrane-bounded organelle
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000330258
- Coding exons
- 1
- Length
- 20628
- Individuals with no LoFs
- 125690
- Homozygous LoFs
- 2
- Heterozygous LoFs
- 6
- Defined
- 125698
- p
- 0.0000318
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.569 | 474 | 440 | 1.08 | 0.0000330 | 7382 |
| Missense (PolyPhen) | 105 | 126.38 | 0.83083 | 2172 | ||
| Synonymous | -1.15 | 181 | 162 | 1.11 | 0.0000114 | 2325 |
| Loss of Function | 4.06 | 5 | 28.3 | 0.177 | 0.00000266 | 424 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.00011 | 0.000087 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000074 | 0.000054 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000050 | 0.000035 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Regulator of the canonical Wnt signaling pathway. Acts by specifically binding phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2), translocating to the cell membrane and interacting with key regulators of the canonical Wnt signaling pathway, such as components of the beta-catenin destruction complex. Acts both as a positive and negative regulator of the Wnt signaling pathway, depending on the context: acts as a positive regulator by promoting LRP6 phosphorylation. Also acts as a negative regulator by acting as a scaffold protein for the beta- catenin destruction complex and promoting stabilization of Axin at the cell membrane. Promotes CTNNB1 ubiquitination and degradation. Involved in kidney development. {ECO:0000269|PubMed:17510365, ECO:0000269|PubMed:17925383, ECO:0000269|PubMed:19416806, ECO:0000269|PubMed:21304492, ECO:0000269|PubMed:21498506}.;
Recessive Scores
- pRec
- 0.0852
Intolerance Scores
- RVIS EVS
- -0.39
- RVIS percentile EVS
- 27.03
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |