HDAC1
protein-codinghistone deacetylase 1, the group of MiDAC complex subunits|SIN3 histone deacetylase complex subunits|Histone deacetylases, class I|NuRD complex subunits|EMSY complex
Gene summary
Histone acetylation and deacetylation, catalyzed by multisubunit complexes, play a key role in the regulation of eukaryotic gene expression. The protein encoded by this gene belongs to the histone deacetylase/acuc/apha family and is a component of the histone deacetylase complex. It also interacts with retinoblastoma tumor-suppressor protein and this complex is a key element in the control of cell proliferation and differentiation. Together with metastasis-associated protein-2, it deacetylates p53 and modulates its effect on cell growth and apoptosis. [provided by RefSeq, Jul 2008]
- RPD3L1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~41.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0005453
Submitter: ClinGen
HDAC1 was reported in relation to autosomal dominant congenital heart disease in 2007 (Montgomery et al., PMID: 17639084). No genetic evidence linking HDAC1 was identified in the literature or elsewhere. There was no scorable experimental evidence either. The sole source of experimental evidence analyzed was a mouse model (PMID: 17639084), which was considered non-scorable as there was no genetic evidence and the mice did not recapitulate the specific phenotype of congenital heart disease. In summary, the evidence supporting the relationship between HDAC1 and autosomal dominant congenital heart disease has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role HDAC1 plays in this disease. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date January 8th, 2024 (SOP Version 10).
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to HDAC1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_004964.3. 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 | 2 | 2 | 2 | 6 | ||
| missense | 1 | 34 | 35 | |||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 6 | 6 | ||||
| Total | 0 | 1 | 43 | 2 | 2 | 48 |
Highest pathogenic variant AF is 6.8406e-7
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_004955.2 | 14 | MANE Select | |
| Ensembl | ENSP00000362649.3 | 14 | MANE Select | |
| Ensembl | ENSP00000407859.1 | 6 | Standard | |
| Ensembl | ENSP00000520718.1 | 7 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| hdac1 | Danio rerio | Structure: endodermal cell Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Chronic myeloid leukemia - Homo sapiens (human)
- Cell cycle - Homo sapiens (human)
- Longevity regulating pathway - multiple species - Homo sapiens (human)
- Huntington,s disease - Homo sapiens (human)
- Thyroid hormone signaling pathway - Homo sapiens (human)
Biological Process
- negative regulation of transcription by RNA polymerase II
- chromatin organization
- chromatin remodeling
- methylation-dependent chromatin silencing
- protein deacetylation
Molecular Function
- transcription regulatory region sequence-specific DNA binding
- RNA polymerase II proximal promoter sequence-specific DNA binding
- RNA polymerase II distal enhancer sequence-specific DNA binding
- core promoter sequence-specific DNA binding
- RNA polymerase II transcription factor binding
Cellular Component
- histone deacetylase complex
- chromatin
- nuclear chromatin
- heterochromatin
- nucleus
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000373548
- Coding exons
- 14
- Length
- 41550
- Individuals with no LoFs
- 125732
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 16
- Defined
- 125748
- p
- 0.0000636
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.04 | 147 | 293 | 0.501 | 0.0000173 | 3206 |
| Missense (PolyPhen) | 28 | 77.811 | 0.35985 | 949 | ||
| Synonymous | 1.76 | 92 | 116 | 0.792 | 0.00000774 | 854 |
| Loss of Function | 3.98 | 6 | 29.3 | 0.205 | 0.00000158 | 347 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000080 | 0.000079 | rare |
| South Asian | 0.00013 | 0.00013 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Deacetylates SP proteins, SP1 and SP3, and regulates their function. Component of the BRG1-RB1-HDAC1 complex, which negatively regulates the CREST- mediated transcription in resting neurons. Upon calcium stimulation, HDAC1 is released from the complex and CREBBP is recruited, which facilitates transcriptional activation. Deacetylates TSHZ3 and regulates its transcriptional repressor activity. Deacetylates 'Lys-310' in RELA and thereby inhibits the transcriptional activity of NF-kappa-B. Deacetylates NR1D2 and abrogates the effect of KAT5-mediated relieving of NR1D2 transcription repression activity. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development. Involved in CIART-mediated transcriptional repression of the circadian transcriptional activator: CLOCK-ARNTL/BMAL1 heterodimer. Required for the transcriptional repression of circadian target genes, such as PER1, mediated by the large PER complex or CRY1 through histone deacetylation. {ECO:0000269|PubMed:12837748, ECO:0000269|PubMed:16478997, ECO:0000269|PubMed:17000776, ECO:0000269|PubMed:17704056, ECO:0000269|PubMed:17996965, ECO:0000269|PubMed:19081374, ECO:0000269|PubMed:19343227}.;
Recessive Scores
- pRec
- 0.919
Intolerance Scores
- LoFtool
- 0.449
- RVIS EVS
- -0.69
- RVIS percentile EVS
- 14.97
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- K
- Indispensability pred.
- E
- Indispensability score
- 0.811
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |