H4C5
protein-codingH4 clustered histone 5, the group of H4 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 is intronless and encodes a replication-dependent histone that is a member of the histone H4 family. Transcripts from this gene lack polyA tails but instead contain a palindromic termination element. This gene is found in the large histone gene cluster on chromosome 6. [provided by RefSeq, Aug 2015]
- H4FJ
- HIST1H4E
MANE transcript
Inheritance
ClinVar variants
Top phenotype
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~0.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0030993
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0030993
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0030993
Submitter: ClinGen
The H4C5 gene is located on chromosome 6 at 6p22.2 and encodes the H4 clustered histone 5 protein, a core component of nucelosomes. H4C5 was first reported in relation to autosomal dominant Tessadori-Bicknell-van Haaften neurodevelopmental syndrome 3 (TEVANED3) in 2022 (Tessadori et al., PMID: 35202563). TEVANED3 is characterized by intellectual disability/global developmental delay, hypotonia, seizure, microcephaly and short stature. To date, 7 missense variants, including 4 unique and 3 recurrent variants in 18 probands have been reported in two publications and are included in this curation (PMID 35202563; 36987712). Experimental evidence to support this gene-disease relationship association is from expression and protein interaction data at present. In summary, there is strong evidence to support the relationship between H4C5 and autosomal dominant TEVANED3. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date March 19, 2024 (SOP Version 10.0).
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Musculoskeletal; Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to H4C5 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_003545.4. 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 | 5 | 1 | 6 | |||
| missense | 5 | 7 | 33 | 45 | ||
| nonsense | 0 | |||||
| start loss | 1 | 1 | ||||
| frameshift | 4 | 1 | 5 | |||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 5 | 7 | 38 | 6 | 1 | 57 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_003536.1 | 1 | MANE Select | |
| Ensembl | ENSP00000484789.1 | 1 | MANE Select |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Systemic lupus erythematosus - Homo sapiens (human)
- Viral carcinogenesis - Homo sapiens (human)
- Alcoholism - Homo sapiens (human)
- Histone Modifications
- HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA)
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Core component of nucleosome. 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.;
- Disease
- DISEASE: Note=Chromosomal aberrations involving HISTONE H4 is a cause of B-cell non-Hodgkin lymphomas (B-cell NHL). Translocation t(3;6)(q27;p21), with BCL6. {ECO:0000269|PubMed:12414651}.;
Intolerance Scores
- LoFtool
- 0.576
- RVIS EVS
- -0.38
- RVIS percentile EVS
- 27.42
Essentials
- Essential (CRISPR)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 1.00
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |