GeneBe

HOXA1

protein-coding

homeobox A1, the group of HOXL subclass homeoboxes

Gene summary

In vertebrates, the genes encoding the class of transcription factors called homeobox genes are found in clusters named A, B, C, and D on four separate chromosomes. Expression of these proteins is spatially and temporally regulated during embryonic development. This gene is part of the A cluster on chromosome 7 and encodes a DNA-binding transcription factor which may regulate gene expression, morphogenesis, and differentiation. The encoded protein may be involved in the placement of hindbrain segments in the proper location along the anterior-posterior axis during development. Two transcript variants encoding two different isoforms have been found for this gene, with only one of the isoforms containing the homeodomain region. [provided by RefSeq, Jul 2008]

Previous symbols:
  • HOX1F
  • HOX1

MANE transcript

NM_005522.5

Inheritance

AR

ClinVar variants

P:5U:68B:21

Top phenotype

Athabaskan brainstem dysgenesis syndrome; Bosley-Salih-Alorainy syndrome

gnomAD constraint

pLI —, LoF o/e 0.24

Max pathogenic AF

—

Genomic locus

chr7:27,092,993-27,096,000

External References & Databases

Ensembl (ENSG00000105991)NCBI Gene (3198)OMIM (142955)HGNC:5099GenCCUniProt (P49639)AlphaFoldClinVar (HOXA1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~3.0 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

syndromic intellectual disabilitySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0000508

Submitter: PanelApp Australia

HOXA1-related syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011099

Submitter: G2P

syndromic intellectual disabilityDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0000508

Submitter: ClinGen

Variants in HOXA1 were first reported in humans with autosomal recessive syndromic intellectual disability as early as 2003 (Holve et al., PMID:12833395). Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least 4 variants (e.g. nonsense and frameshift) have been reported in humans. Variants in this gene have been reported in at least 16 probands in 3 publications (12833395, 16155570, 18412118). Variants in this gene segregated with disease in 8 additional family members. All affected individuals identified thus far are Saudi Arabian, Turkish, or Native American, and the authors asserted that the variants associated were likely founder variants. The mechanism for disease is homozygous loss of function. Of note, this gene has also been implicated in brain malformation. This will be assessed separately. This gene-disease association is supported by expression studies and animal models. In summary, HOXA1 is definitively associated with autosomal recessive syndromic intellectual disability. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 6/19/19 (SOP Version 6).

HOXA1-related syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0011099

Submitter: Ambry Genetics

HOXA1-related syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011099

Submitter: Orphanet

HOXA1-related syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011099

Submitter: Labcorp Genetics (formerly Invitae)

Bosley-Salih-Alorainy syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019075

Submitter: Orphanet

Clinical Genomic Database (CGD)

Athabaskan brainstem dysgenesis syndrome; Bosley-Salih-Alorainy syndromeAR

Manifestation: Audiologic/Otolaryngologic; Cardiovascular; Craniofacial; Neurologic

Intervention: Audiologic/Otolaryngologic; Cardiovascular

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; The conditions can involve congenital cardiac anomalies, and awareness may allow early management

Refs: 16155570; 18412118; 20075099Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HOXA1 variants in ClinVar

7 Conditions Cataloged
Inborn genetic diseasesTotal: 77
not providedTotal: 20
Athabaskan Brain Stem Dysgenesis Syndrome (ABDS)Total: 11
not specifiedTotal: 10
HOXA1-related syndromeTotal: 9
Bosley-Salih-Alorainy syndromeTotal: 3
Intellectual disabilityTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005522.5. 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.

EffectPLPVUSLBBSum
synonymous
4
clinvar
15
clinvar
2
clinvar
 21
missense
64
clinvar
3
clinvar
1
clinvar
 68
nonsense
2
clinvar
1
clinvar
 3
start loss
0
frameshift
2
clinvar
 2
splice donor/acceptor (+/-2bp)
0
Total416818394

Highest pathogenic variant AF is 0.0000065725476

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_005522.5RefSeqNP_005513.22MANE Select
ENST00000643460.2EnsemblENSP00000494260.22MANE Select
NM_153620.3RefSeqNP_705873.32Standard
ENST00000355633.5EnsemblENSP00000347851.52Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Neural Crest Differentiation
  • Endoderm Differentiation
  • Activation of anterior HOX genes in hindbrain development during early embryogenesis

Biological Process

  • multicellular organism development
  • sensory perception of sound
  • optokinetic behavior
  • anatomical structure morphogenesis
  • abducens nerve formation

Molecular Function

  • DNA-binding transcription factor activity, RNA polymerase II-specific
  • DNA-binding transcription activator activity, RNA polymerase II-specific
  • protein binding
  • identical protein binding
  • sequence-specific DNA binding

Cellular Component

  • nucleus

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000343060
Coding exons
2
Length
3004
Individuals with no LoFs
125736
Homozygous LoFs
0
Heterozygous LoFs
12
Defined
125748
p
0.0000477
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.1031961921.020.00001052178
Missense (PolyPhen)10298.1881.03881152
Synonymous-0.7329384.41.100.00000516686
Loss of Function2.46312.30.2435.97e-7134

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000580.000058rare
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish0.0000460.000046rare
European (Non-Finnish)0.0000530.000053rare
South Asian0.0000330.000033rare
Other0.000330.00033rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Sequence-specific transcription factor (By similarity). Regulates multiple developmental processes including brainstem, inner and outer ear, abducens nerve and cardiovascular development and morphogenesis as well as cognition and behavior (PubMed:16155570). Also part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis. Acts on the anterior body structures. Seems to act in the maintenance and/or generation of hindbrain segments (By similarity). Activates transcription in the presence of PBX1A and PKNOX1 (By similarity). {ECO:0000250|UniProtKB:P09022, ECO:0000250|UniProtKB:Q90423, ECO:0000269|PubMed:16155570}.;
Disease
DISEASE: Athabaskan brainstem dysgenesis syndrome (ABDS) [MIM:601536]: Characterized by horizontal gaze palsy, sensorineural deafness, central hypoventilation, and developmental delay. Some patients had swallowing dysfunction, vocal cord paralysis, facial paresis, seizures, and cardiac outflow tract anomalies. {ECO:0000269|PubMed:16155570}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Bosley-Salih-Alorainy syndrome (BSAS) [MIM:601536]: A disease characterized by horizontal gaze abnormalities, deafness, facial weakness, vascular malformations of the internal carotid arteries and cardiac outflow trac. Some patients manifest mental retardation and autism spectrum disorder. Affected individuals do not suffer from central hypoventilation. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.229

Intolerance Scores

LoFtool
0.215
RVIS EVS
0.06
RVIS percentile EVS
58.74

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.962

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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