H4C3

protein-coding

H4 clustered histone 3, 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]

Previous symbols:

H4FG
HIST1H4C

MANE transcript

NM_003542.4

Inheritance

ClinVar variants

P:10U:42B:12

Top phenotype

Tessadori-Bicknell-van Haaften neurodevelopmental syndrome 1

gnomAD constraint

pLI —, LoF o/e 2.07

Max pathogenic AF

—

Genomic locus

chr6:26,103,933-26,104,337

External References & Databases

Ensembl (ENSG00000197061)

Transcript & Mutation Effects

hg38 • Region Span ~0.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Tessadori-van Haaften neurodevelopmental syndrome 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030729

Submitter: PanelApp Australia

Tessadori-van Haaften neurodevelopmental syndrome 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030729

Submitter: G2P

Tessadori-van Haaften neurodevelopmental syndrome 1MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0030729

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Tessadori-Bicknell-van Haaften neurodevelopmental syndrome 1AD

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

Refs: 28920961

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to H4C3 variants in ClinVar

7 Conditions Cataloged

not specifiedTotal: 29

not providedTotal: 22

Tessadori-van Haaften neurodevelopmental syndrome 1Total: 10

H4C3-related disorderTotal: 7

HIST1H4C-related disordersTotal: 1

Global developmental delayTotal: 1

HIST1H4C-associated disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003542.4. 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				8 clinvar	4 clinvar	12
missense	3 clinvar	5 clinvar	38 clinvar			46
nonsense		1 clinvar	1 clinvar			2
start loss						0
frameshift	1 clinvar		3 clinvar			4
splice donor/acceptor (+/-2bp)						0
Total	4	6	42	8	4	64

Highest pathogenic variant AF is 6.9637497e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003542.4	RefSeq	NP_003533.1	1	MANE Select
ENST00000377803.4	Ensembl	ENSP00000367034.3	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)

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000377803
Coding exons: 1
Length: 415
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0165	67	66.6	1.01	0.00000304	644
Missense (PolyPhen)		13	18.793	0.69174		208
Synonymous	-8.71	80	24.8	3.23	0.00000111	233
Loss of Function	-1.38	4	1.93	2.07	8.53e-8	26

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
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: 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: 0.565
RVIS EVS: -0.34
RVIS percentile EVS: 30.07

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.975

Gene Damage Prediction

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