H3C4

protein-coding

H3 clustered histone 4, 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 is intronless and encodes a replication-dependent histone that is a member of the histone H3 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]

Previous symbols:

H3FB
HIST1H3D

MANE transcript

NM_001376937.1

Inheritance

—

ClinVar variants

U:17B:1

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 1.15

Max pathogenic AF

—

Genomic locus

chr6:26,195,164-26,197,286

External References & Databases

Ensembl (ENSG00000197409)

Transcript & Mutation Effects

hg38 • Region Span ~2.1 kb

Loading mutation effect viewer...

GenCC 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 H3C4 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 15

not providedTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001376937.1. 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 clinvar		1
missense			17 clinvar			17
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	17	1	0	18

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 4 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001376937.1	RefSeq	NP_001363866.1	1	MANE Select
ENST00000356476.3	Ensembl	ENSP00000366999.2	1	MANE Select
NM_003530.4	RefSeq	NP_003521.2	1	Standard
ENST00000718271.1	Ensembl	ENSP00000520711.1	1	Standard

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)
Histone Modifications
B-WICH complex positively regulates rRNA expression

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000377831
Coding exons: 1
Length: 2454
Individuals with no LoFs: 125722
Homozygous LoFs: 0
Heterozygous LoFs: 26
Defined: 125748
p: 0.000103

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.384	75	85.0	0.883	0.00000393	857
Missense (PolyPhen)		25	31.043	0.80534		334
Synonymous	-4.81	72	35.5	2.03	0.00000165	312
Loss of Function	-0.261	4	3.47	1.15	1.52e-7	35

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
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)	0.000053	0.000053	rare
South Asian	0.00052	0.00052	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

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: 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:22286216}. Note=The gene represented in this entry is involved in disease pathogenesis. HIST1H3B mutations affecting residue Lys-28 involved in post-translational modifications of histone H3.1 are recurrent in malignant, aggressive gliomas including pediatric non-brain stem glioblastoma and diffuse intrinsic pontine glioma (DIPG) (PubMed:22286216). The mechanism through which mutations lead to tumorigenesis involves altered histone methylation, impaired regulation of Polycomb repressive complex 2 (PRC2) activity, and aberrant epigenetic regulation of gene expression (PubMed:23603901). {ECO:0000269|PubMed:22286216, ECO:0000269|PubMed:23603901}.; DISEASE: Note=HIST1H3B or HIST1H3C mutations affecting residue Lys-37 of histone H3.1 are involved in the pathogenesis of pediatric undifferentiated soft tissue sarcomas. The mechanism through which mutations lead to tumorigenesis involves altered histones methylation with gain of global H3K27 methylation, altered Polycomb repressive complex 1 (PRC1) activity, aberrant epigenetic regulation of gene expression and impaired differentiation of mesenchimal progenitor cells. {ECO:0000269|PubMed:27174990}.;

Intolerance Scores

LoFtool: 0.321
RVIS EVS: -0.14
RVIS percentile EVS: 42.88

Essentials

Essential (CRISPR): N
Indispensability pred.: E
Indispensability score: 0.999

Gene Damage Prediction

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