GeneBe

H3-3A

protein-coding

H3.3 histone A, the group of H3 histones

Gene summary

Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Two molecules of each of the four core histones (H2A, H2B, H3, and H4) form an octamer, around which approximately 146 bp of DNA is wrapped in repeating units, called nucleosomes. The linker histone, H1, interacts with linker DNA between nucleosomes and functions in the compaction of chromatin into higher order structures. This gene contains introns and its mRNA is polyadenylated, unlike most histone genes. The protein encoded is a replication-independent member of the histone H3 family. [provided by RefSeq, Jul 2008]

Previous symbols:
  • H3F3
  • H3F3A

MANE transcript

NM_002107.7

Inheritance

AD

ClinVar variants

P:24U:34B:5

Top phenotype

Bryant-Li-Bhoj neurodevelopmental syndrome 1

gnomAD constraint

pLI —, LoF o/e 0.37

Max pathogenic AF

—

Genomic locus

chr1:226,061,851-226,072,019

External References & Databases

Ensembl (ENSG00000163041)NCBI Gene (3020)OMIM (601128)HGNC:4764GenCCUniProt (P84243)AlphaFoldClinVar (H3-3A)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~10.2 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Bryant-Li-Bhoj neurodevelopmental syndrome 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0030606

Submitter: ClinGen

The *H3-3A* gene is located on chromosome 1 at 1q42.12 and encodes for a 135-amino acid protein named H3.3. H3.3 protein is a replication-independent variant of H3 histone that is expressed throughout the cell cycle. H3.3 supports chromosomal heterochromatic structures thus maintaining genome integrity during mammalian development and influences gene transcription/expression via post-translational modifications on histones. *H3-3A* was first reported in relation to autosomal dominant Bryant-Li-Bhoj neurodevelopmental syndrome 1 in 2020 (Bryant et al., PMID: 33268356). Bryant et al. demonstrated the presence of de novo heterozygous germline missense variants in H3-3A (n=33) or H3-3B (n=13) in a cohort of 46 unrelated patients (PMID: 33268356). These individuals have core phenotypes of neurologic dysfunction with brain anomalies and congenital anomalies with some individuals (5 of 33) with *H3-3A* variants showing progressive neurologic disease or regression. 25 unique missense variants have been reported in 35 patients, of which four are recurrent variants (p.Arg18Gly, p.Thr46Ile, p.Arg84Cys, p.Gln126Arg). Evidence supporting this gene-disease relationship includes case-level and experimental data. Heterozygous missense variants in *H3-3A* were identified in at least 35 unrelated patients with clinical features suggestive of autosomal dominant Bryant-Li-Bhoj neurodevelopmental syndrome 1 (Maver et al 2019, PMID: 31942419; Bryant et al 2020, PMID: 33268356; Okur et al 2021, PMID: 34876591). This gene-disease association is supported by biochemical function, gene expression, protein interaction, non-human model organism (zebrafish) studies (Cox et al 2012, PMID: 23028350; Funk et al 2022, PMID:35930666; Di Liegro et al 2023, PMID:37446205; Tagami et al 2004, PMID: 14718166). In summary, the *H3-3A* gene is definitively associated with autosomal dominant Bryant-Li-Bhoj neurodevelopmental syndrome 1. 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 Syndromic Disorders GCEP on the meeting date March 19, 2024 (SOP Version 10).

Bryant-Li-Bhoj neurodevelopmental syndrome 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0030606

Submitter: Illumina

Bryant-Li-Bhoj neurodevelopmental syndrome 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030606

Submitter: G2P

Bryant-Li-Bhoj neurodevelopmental syndrome 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030606

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Bryant-Li-Bhoj neurodevelopmental syndrome 1AD

Manifestation: Audiologic/Otolaryngologic; Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 33268356; 34876591Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to H3-3A variants in ClinVar

13 Conditions Cataloged
not providedTotal: 33
Bryant-Li-Bhoj neurodevelopmental syndrome 1Total: 22
not specifiedTotal: 12
Inborn genetic diseasesTotal: 7
Global developmental delayTotal: 6
H3-3A-related disorderTotal: 6
Intellectual disabilityTotal: 6
Delayed speech and language developmentTotal: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002107.7. 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
 4
missense
6
clinvar
18
clinvar
32
clinvar
1
clinvar
 57
nonsense
0
start loss
0
frameshift
1
clinvar
 1
splice donor/acceptor (+/-2bp)
1
clinvar
 1
Total618345063

Highest pathogenic variant AF is 0.0000015757909

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 115 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_002107.7RefSeqNP_002098.13MANE Select
ENST00000366815.10EnsemblENSP00000355780.33MANE Select
NM_001379043.1RefSeqNP_001365972.13Standard
NM_001379045.1RefSeqNP_001365974.13Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
h3f3aDanio rerio

Structure: melanocyte

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Systemic lupus erythematosus - Homo sapiens (human)
  • Transcriptional misregulation in cancer - Homo sapiens (human)
  • Alcoholism - Homo sapiens (human)
  • Gastric Cancer Network 1
  • Histone Modifications

Biological Process

  • chromatin silencing at rDNA
  • osteoblast differentiation
  • nucleosome assembly
  • DNA replication-independent nucleosome assembly
  • nucleus organization

Molecular Function

  • RNA polymerase II core promoter sequence-specific DNA binding
  • RNA polymerase II distal enhancer sequence-specific DNA binding
  • protein binding
  • nucleosomal DNA binding
  • protein heterodimerization activity

Cellular Component

  • nuclear chromosome
  • nuclear chromosome, telomeric region
  • nucleosome
  • nuclear nucleosome
  • Barr body

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000366813
Coding exons
3
Length
10151
Individuals with no LoFs
125293
Homozygous LoFs
0
Heterozygous LoFs
2
Defined
125295
p
0.00000798
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense3.16588.60.05640.00000561862
Missense (PolyPhen)012.390184
Synonymous-0.3283027.81.080.00000143298
Loss of Function1.3625.400.3703.10e-763

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000200.000018rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Variant histone H3 which replaces conventional H3 in a wide range of nucleosomes in active genes. Constitutes the predominant form of histone H3 in non-dividing cells and is incorporated into chromatin independently of DNA synthesis. Deposited at sites of nucleosomal displacement throughout transcribed genes, suggesting that it represents an epigenetic imprint of transcriptionally active chromatin. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling. {ECO:0000269|PubMed:14718166, ECO:0000269|PubMed:15776021, ECO:0000269|PubMed:16258499}.;
Disease
DISEASE: Glioma (GLM) [MIM:137800]: Gliomas are benign or malignant central nervous system neoplasms derived from glial cells. They comprise astrocytomas and glioblastoma multiforme that are derived from astrocytes, oligodendrogliomas derived from oligodendrocytes and ependymomas derived from ependymocytes. {ECO:0000269|PubMed:22286061, ECO:0000269|PubMed:22286216, ECO:0000269|PubMed:23539269}. Note=The gene represented in this entry is involved in disease pathogenesis. H3F3A mutations affecting residues involved in post-translational modifications of histone H3.3 are recurrent in malignant, aggressive gliomas including glioblastoma multiforme (GBM) and diffuse intrinsic pontine glioma (DIPG) (PubMed:22286061, PubMed:22286216). The mechanism through which mutations lead to tumorigenesis involves altered histones methylation, impaired regulation of Polycomb repressive complex 2 (PRC2) activity, and aberrant epigenetic regulation of gene expression (PubMed:23539269, PubMed:23539183, PubMed:23603901). {ECO:0000269|PubMed:22286061, ECO:0000269|PubMed:22286216, ECO:0000269|PubMed:23539183, ECO:0000269|PubMed:23539269, ECO:0000269|PubMed:23603901}.; DISEASE: Note=H3F3A and H3F3B mutations affecting residues involved in post-translational modifications of histone H3.3 are implicated in the pathogenesis of some bone and cartilage neoplasms. Mutations have been found with high prevalence in chondroblastoma and giant cell tumors of bone, and with low frequency in osteosarcoma, conventional chondrosarcoma and clear cell chondrosarcoma. Chondroblastoma samples frequently carry a H3F3B mutation affecting residue Lys-37 (H3K36), although H3F3A is mutated in some cases. Most giant cell tumors of bone harbor H3F3A mutations affecting residue Gly-35 (H3G34). {ECO:0000269|PubMed:24162739}.;

Recessive Scores

pRec
0.174

Intolerance Scores

LoFtool
0.264
RVIS EVS
0.15
RVIS percentile EVS
63.81

Essentials

Essential (CRISPR)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.924

Gene Damage Prediction

AllRecessiveDominant
MendelianLowLowLow
Primary ImmunodeficiencyLowLowLow
CancerLowLowLow
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