HAP1
protein-codinghuntingtin associated protein 1
Gene summary
Huntington's disease (HD), a neurodegenerative disorder characterized by loss of striatal neurons, is caused by an expansion of a polyglutamine tract in the HD protein huntingtin. This gene encodes a protein that interacts with huntingtin, with two cytoskeletal proteins (dynactin and pericentriolar autoantigen protein 1), and with a hepatocyte growth factor-regulated tyrosine kinase substrate. The interactions with cytoskeletal proteins and a kinase substrate suggest a role for this protein in vesicular trafficking or organelle transport. Several alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]
- HAP2
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~16.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
No GenCC data available for this gene.
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to HAP1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_177977.3. 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 | 1 | 4 | 2 | 7 | ||
| missense | 107 | 12 | 5 | 124 | ||
| nonsense | 1 | 2 | 3 | |||
| start loss | 0 | |||||
| frameshift | 3 | 3 | ||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 0 | 0 | 112 | 16 | 9 | 137 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_817084.2 | 11 | MANE Select | |
| Ensembl | ENSP00000334002.4 | 11 | MANE Select | |
| RefSeq | NP_001073339.1 | 10 | Standard | |
| RefSeq | NP_001073340.1 | 10 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- GABAergic synapse - Homo sapiens (human)
- Huntington,s disease - Homo sapiens (human)
Biological Process
- protein targeting
- exocytosis
- autophagy
- chemical synaptic transmission
- brain development
Molecular Function
- signaling receptor binding
- protein binding
- myosin binding
- ion channel binding
- brain-derived neurotrophic factor binding
Cellular Component
- nucleus
- cytoplasm
- mitochondrion
- lysosome
- autophagosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000347901
- Coding exons
- 11
- Length
- 16903
- Individuals with no LoFs
- 125375
- Homozygous LoFs
- 1
- Heterozygous LoFs
- 372
- Defined
- 125748
- p
- 0.00148
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.0877 | 354 | 349 | 1.01 | 0.0000192 | 3931 |
| Missense (PolyPhen) | 20 | 23.997 | 0.83345 | 246 | ||
| Synonymous | -0.845 | 165 | 152 | 1.09 | 0.00000864 | 1229 |
| Loss of Function | -1.17 | 35 | 28.3 | 1.24 | 0.00000121 | 340 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00094 | 0.00092 | rare |
| Latino/Admixed American | 0.00026 | 0.00026 | rare |
| Ashkenazi Jewish | 0.0020 | 0.0020 | notable |
| East Asian | 0.011 | 0.011 | notable |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00056 | 0.00054 | rare |
| South Asian | 0.0021 | 0.0020 | notable |
| Other | 0.00065 | 0.00065 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Originally identified as neuronal protein that specifically associates with HTT/huntingtin and the binding is enhanced by an expanded polyglutamine repeat within HTT possibly affecting HAP1 interaction properties. Both HTT and HAP1 are involved in intracellular trafficking and HAP1 is proposed to link HTT to motor proteins and/or transport cargos. Seems to play a role in vesicular transport within neurons and axons such as from early endosomes to late endocytic compartments and to promote neurite outgrowth. The vesicular transport function via association with microtubule-dependent transporters can be attenuated by association with mutant HTT. Involved in the axonal transport of BDNF and its activity-dependent secretion; the function seems to involve HTT, DCTN1 and a complex with SORT1. Involved in APP trafficking and seems to facilitate APP anterograde transport and membrane insertion thereby possibly reducing processing into amyloid beta. Involved in delivery of gamma-aminobutyric acid (GABA(A)) receptors to synapses; the function is dependent on kinesin motor protein KIF5 and is disrupted by HTT with expanded polyglutamine repeat. Involved in regulation of autophagosome motility by promoting efficient retrograde axonal transport. Seems to be involved in regulation of membrane receptor recycling and degradation, and respective signal transduction, including GABA(A) receptors, tyrosine kinase receptors, EGFR, IP3 receptor and androgen receptor. Among others suggested to be involved in control of feeding behavior (involving hypothalamic GABA(A) receptors), cerebellar and brainstem development (involving AHI1 and NTRK1/TrkA), postnatal neurogenesis (involving hypothalamic NTRK2/TrkB), and ITPR1/InsP3R1-mediated Ca(2+) release (involving HTT and possibly the effect of mutant HTT). Via association with DCTN1/dynactin p150-glued and HTT/huntingtin involved in cytoplasmic retention of REST in neurons. May be involved in ciliogenesis. Involved in regulation of exocytosis. Seems to be involved in formation of cytoplasmic inclusion bodies (STBs). In case of anomalous expression of TBP, can sequester a subset of TBP into STBs; sequestration is enhanced by an expanded polyglutamine repeat within TBP. HAP1-containing STBs have been proposed to play a protective role against neurodegeneration in Huntigton disease (HD) and spinocerebellar ataxia 17 (SCA17). {ECO:0000269|PubMed:18922795}.;
Intolerance Scores
- LoFtool
- 0.998
- RVIS EVS
- 1.87
- RVIS percentile EVS
- 97.21
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.350
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | High |
| Cancer | High | Medium | High |