ALX1
protein-codingALX homeobox 1, the group of PRD class homeoboxes and pseudogenes
Gene summary
The specific function of this gene has yet to be determined in humans; however, in rodents, it is necessary for survival of the forebrain mesenchyme and may also be involved in development of the cervix. Mutations in the mouse gene lead to neural tube defects such as acrania and meroanencephaly. [provided by RefSeq, Jul 2008]
- CART1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~21.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0013271
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0013271
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0013271
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013271
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0013271
Submitter: ClinGen
*ALX1* has been repeatedly described in association with autosomal recessive frontonasal dysplasia 3. Frontonasal dysplasia 3 presents as a severe form of frontonasal dysplasia characterized by hypertelorism, bilateral extreme microphthalmia, upper eyelid coloboma, sparse eyelashes, absence of eyebrows, wide nasal base, hypoplasia of the ala nasi, bilateral non-midline cleft lip with a prominent glabella, complete cleft palate, and low-set posteriorly angulated ears. At least 2 splice site and 1 missense mutation have been reported in at least 3 probands from 3 publications (PMIDs:20451171,27324866,32914578) Variants in this gene have been also seen to segregation in two families (PMIDs:27324866, 32914578,) This gene disease association is also supported by animal models (PMIDs:8673125, 23059813). In summary *ALX1* is definitively associated with autosomal recessive Frontonasal dysplasia 3. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Craniofacial Malformations Gene Curation Expert Panel on 10/13/2022. (SOP Version 9)
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic
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 ALX1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_006982.3. 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 | 11 | 2 | 13 | |||
| missense | 38 | 5 | 2 | 45 | ||
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 2 | 2 | ||||
| Total | 2 | 1 | 38 | 16 | 4 | 61 |
Highest pathogenic variant AF is 6.8448236e-7
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_008913.2 | 4 | MANE Select | |
| Ensembl | ENSP00000315417.3 | 4 | MANE Select | |
| Ensembl | ENSP00000806435.1 | 4 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| alx1 | Danio rerio | Structure: cranial neural crest cell Quality: mislocalised abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- negative regulation of transcription by RNA polymerase II
- cartilage condensation
- neural crest cell migration
- neural tube closure
- transcription by RNA polymerase II
Molecular Function
- RNA polymerase II regulatory region sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA-binding transcription activator activity, RNA polymerase II-specific
- DNA-binding transcription factor activity
- transcription corepressor activity
Cellular Component
- nucleus
- nucleoplasm
- transcription factor complex
- Golgi apparatus
- nuclear body
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000316824
- Coding exons
- 4
- Length
- 21678
- Individuals with no LoFs
- 125737
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 5
- Defined
- 125742
- p
- 0.0000199
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.0961 | 183 | 187 | 0.980 | 0.00000962 | 2164 |
| Missense (PolyPhen) | 37 | 44.684 | 0.82805 | 518 | ||
| Synonymous | -0.249 | 74 | 71.3 | 1.04 | 0.00000374 | 616 |
| Loss of Function | 2.64 | 4 | 15.1 | 0.265 | 9.10e-7 | 152 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000018 | 0.000018 | rare |
| South Asian | 0.000066 | 0.000065 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Sequence-specific DNA-binding transcription factor that binds palindromic sequences within promoters and may activate or repress the transcription of a subset of genes (PubMed:9753625, PubMed:8756334). Most probably regulates the expression of genes involved in the development of mesenchyme-derived craniofacial structures. Early on in development, it plays a role in forebrain mesenchyme survival (PubMed:20451171). May also induce epithelial to mesenchymal transition (EMT) through the expression of SNAI1 (PubMed:23288509). {ECO:0000269|PubMed:20451171, ECO:0000269|PubMed:23288509, ECO:0000269|PubMed:8756334, ECO:0000269|PubMed:9753625}.;
- Disease
- DISEASE: Frontonasal dysplasia 3 (FND3) [MIM:613456]: The term frontonasal dysplasia describes an array of abnormalities affecting the eyes, forehead and nose and linked to midfacial dysraphia. The clinical picture is highly variable. Major findings include true ocular hypertelorism; broadening of the nasal root; median facial cleft affecting the nose and/or upper lip and palate; unilateral or bilateral clefting of the alae nasi; lack of formation of the nasal tip; anterior cranium bifidum occultum; a V-shaped or widow's peak frontal hairline. {ECO:0000269|PubMed:20451171}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.103
Intolerance Scores
- LoFtool
- 0.161
- RVIS EVS
- 0.31
- RVIS percentile EVS
- 72.38
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.871
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |