HDAC3

protein-coding

histone deacetylase 3, the group of Histone deacetylases, class I|NCoR/SMRT transcriptional repression complex subunits

Gene summary

Histones play a critical role in transcriptional regulation, cell cycle progression, and developmental events. Histone acetylation/deacetylation alters chromosome structure and affects transcription factor access to DNA. The protein encoded by this gene belongs to the histone deacetylase/acuc/apha family. It has histone deacetylase activity and represses transcription when tethered to a promoter. It may participate in the regulation of transcription through its binding with the zinc-finger transcription factor YY1. This protein can also down-regulate p53 function and thus modulate cell growth and apoptosis. This gene is regarded as a potential tumor suppressor gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_003883.4

Inheritance

ClinVar variants

P:2U:38B:4

Top phenotype

neurodevelopmental disorder

gnomAD constraint

pLI —, LoF o/e 0.21

Max pathogenic AF

—

Genomic locus

chr5:141,620,876-141,636,849

External References & Databases

Ensembl (ENSG00000171720)

Transcript & Mutation Effects

hg38 • Region Span ~16.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorderMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: G2P

neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

complex neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: Ambry Genetics

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HDAC3 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 22

not providedTotal: 11

HDAC3-related disorderTotal: 1

EpendymomaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003883.4. 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				2 clinvar	1 clinvar	3
missense		2 clinvar	30 clinvar		1 clinvar	33
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			8 clinvar			8
Total	0	2	38	2	2	44

Highest pathogenic variant AF is 6.840769e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 77 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003883.4	RefSeq	NP_003874.2	15	MANE Select
ENST00000305264.8	Ensembl	ENSP00000302967.3	15	MANE Select
NM_001355039.2	RefSeq	NP_001341968.1	14	Standard
NM_001355040.2	RefSeq	NP_001341969.1	10	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
hdac3	Danio rerio	Structure: neuromast hair cell Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

hdac3

Danio rerio

Structure: neuromast hair cell

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Thyroid hormone signaling pathway - Homo sapiens (human)
Viral carcinogenesis - Homo sapiens (human)
Alcoholism - Homo sapiens (human)
Human papillomavirus infection - Homo sapiens (human)
Cell Cycle

Biological Process

negative regulation of transcription by RNA polymerase II
positive regulation of protein phosphorylation
chromatin organization
protein deacetylation
circadian rhythm

Molecular Function

chromatin binding
transcription corepressor activity
histone deacetylase activity
protein binding
transcription factor binding

Cellular Component

histone deacetylase complex
nucleus
nucleoplasm
cytoplasm
Golgi apparatus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000305264
Coding exons: 15
Length: 15995
Individuals with no LoFs: 125740
Homozygous LoFs: 0
Heterozygous LoFs: 8
Defined: 125748
p: 0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.72	92	261	0.353	0.0000150	2860
Missense (PolyPhen)		19	117.74	0.16137		1253
Synonymous	0.0170	102	102	0.998	0.00000633	784
Loss of Function	3.93	6	28.7	0.209	0.00000147	311

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0.000033	0.000033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4), and some other non-histone substrates. 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. Participates in the BCL6 transcriptional repressor activity by deacetylating the H3 'Lys- 27' (H3K27) on enhancer elements, antagonizing EP300 acetyltransferase activity and repressing proximal gene expression. Probably participates in the regulation of transcription through its binding to the zinc-finger transcription factor YY1; increases YY1 repression activity. Required to repress transcription of the POU1F1 transcription factor. Acts as a molecular chaperone for shuttling phosphorylated NR2C1 to PML bodies for sumoylation (PubMed:21444723, PubMed:23911289). Contributes, together with XBP1 isoform 1, to the activation of NFE2L2-mediated HMOX1 transcription factor gene expression in a PI(3)K/mTORC2/Akt-dependent signaling pathway leading to endothelial cell (EC) survival under disturbed flow/oxidative stress (PubMed:25190803). {ECO:0000269|PubMed:21444723, ECO:0000269|PubMed:23911289, ECO:0000269|PubMed:25190803}.;

Recessive Scores

pRec: 0.649

Intolerance Scores

LoFtool: 0.329
RVIS EVS: -0.03
RVIS percentile EVS: 51.4

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.946

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium