H4C3

H4 clustered histone 3, the group of H4 histones

Basic information

Region (hg38): 6:26103933-26104337

Previous symbols: [ "H4FG", "HIST1H4C" ]

Links

ENSG00000197061 ∙ NCBI:8364 ∙ OMIM:602827 ∙ HGNC:4787 ∙ Uniprot:P62805 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Tessadori-van Haaften neurodevelopmental syndrome 1 (Moderate), mode of inheritance: AD
• Tessadori-van Haaften neurodevelopmental syndrome 1 (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Tessadori-Bicknell-van Haaften neurodevelopmental syndrome 1	AD	General	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	Craniofacial; Musculoskeletal; Neurologic	28920961

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the H4C3 gene.

• Tessadori-van Haaften neurodevelopmental syndrome 1 (2 variants)
• Global developmental delay (1 variants)
• HIST1H4C-associated disorder (1 variants)
• not provided (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the H4C3 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous					4	4
missense	3	4	15			22
nonsense			1			1
start loss						0
frameshift	1		2			3
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding						0
Total	4	4	18	0	4

Variants in H4C3

This is a list of pathogenic ClinVar variants found in the H4C3 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
6-26103954-G-A		not specified	Uncertain significance (Jan 06, 2025)
6-26103955-G-C		not specified	Uncertain significance (Oct 04, 2022)
6-26103958-G-T			Uncertain significance (Aug 22, 2024)
6-26103959-C-T		H4C3-related disorder	Likely benign (May 10, 2019)
6-26103960-G-T		not specified	Uncertain significance (Dec 27, 2022)
6-26103968-C-A		H4C3-related disorder	Likely benign (Apr 14, 2020)
6-26103970-G-C			Uncertain significance (Jul 01, 2022)
6-26103970-GA-G		not specified	Uncertain significance (Mar 06, 2024)
6-26103976-G-T		not specified	Uncertain significance (Dec 26, 2024)
6-26103981-G-T		not specified	Uncertain significance (Sep 29, 2023)
6-26103989-T-C		H4C3-related disorder	Benign (Nov 12, 2019)
6-26104020-GA-G		Global developmental delay	Pathogenic (-)
6-26104033-G-A		not specified	Uncertain significance (Mar 16, 2022)
6-26104042-A-G			Uncertain significance (Apr 04, 2024)
6-26104045-C-G			Likely pathogenic (Mar 02, 2023)
6-26104045-C-T			Pathogenic (Sep 16, 2023)
6-26104051-T-C			Uncertain significance (Mar 22, 2023)
6-26104052-T-C		H4C3-related disorder	Benign (Jul 13, 2020)
6-26104078-T-A			Uncertain significance (Mar 11, 2024)
6-26104080-A-T		Tessadori-van Haaften neurodevelopmental syndrome 1	Uncertain significance (Jul 21, 2023)
6-26104083-C-A		not specified	Likely pathogenic (Sep 11, 2023)
6-26104103-T-C		H4C3-related disorder	Likely benign (Aug 12, 2019)
6-26104110-A-G			Uncertain significance (Aug 14, 2023)
6-26104116-G-A		not specified	Uncertain significance (Nov 29, 2023)
6-26104127-G-A		H4C3-related disorder	Benign (Mar 21, 2019)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
H4C3	protein_coding	protein_coding	ENST00000377803	1	415

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.000360	0.228	0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.0165	67	66.6	1.01	0.00000304	644
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

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}.
• Pathway: 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);B-WICH complex positively regulates rRNA expression;ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression;Positive epigenetic regulation of rRNA expression;SIRT1 negatively regulates rRNA expression;DNA Repair;NoRC negatively regulates rRNA expression;Negative epigenetic regulation of rRNA expression;Signaling by WNT;Signal Transduction;DNA methylation;Epigenetic regulation of gene expression;Gene expression (Transcription);Nonhomologous End-Joining (NHEJ);DNA Double-Strand Break Repair;Generic Transcription Pathway;Oxidative Stress Induced Senescence;Senescence-Associated Secretory Phenotype (SASP);Cellular Senescence;Homology Directed Repair;SUMOylation of chromatin organization proteins;Cellular responses to stress;Post-translational protein modification;SUMO E3 ligases SUMOylate target proteins;HDACs deacetylate histones;Metabolism of proteins;Reproduction;HDMs demethylate histones;RNA Polymerase I Promoter Clearance;PKMTs methylate histone lysines;RNA Polymerase I Promoter Opening;RNA Polymerase II Transcription;G2/M DNA damage checkpoint;RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function;RMTs methylate histone arginines;Chromatin modifying enzymes;G2/M Checkpoints;Cell Cycle Checkpoints;RNA Polymerase I Transcription;Amyloid fiber formation;RNA Polymerase I Chain Elongation;Meiotic recombination;SUMOylation;Meiotic synapsis;Meiosis;Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3;RHO GTPases activate PKNs;Nucleosome assembly;HATs acetylate histones;Cellular responses to external stimuli;RHO GTPase Effectors;Signaling by Rho GTPases;Packaging Of Telomere Ends;Telomere Maintenance;Chromosome Maintenance;Deposition of new CENPA-containing nucleosomes at the centromere;Condensation of Prophase Chromosomes;Signaling by Nuclear Receptors;Chromatin organization;Mitotic Prophase;M Phase;Estrogen-dependent gene expression;Transcriptional regulation by small RNAs;RUNX1 regulates transcription of genes involved in differentiation of HSCs;Cell Cycle;Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks;DNA Double Strand Break Response;Cell Cycle, Mitotic;ESR-mediated signaling;Transcriptional regulation by RUNX1;Processing of DNA double-strand break ends;Formation of the beta-catenin:TCF transactivating complex;TCF dependent signaling in response to WNT;Signaling events mediated by HDAC Class III;Gene Silencing by RNA;PRC2 methylates histones and DNA (Consensus)

Intolerance Scores

• loftool: 0.565
• rvis_EVS: -0.34
• rvis_percentile_EVS: 30.07

Haploinsufficiency Scores

• pHI: 0.343
• hipred: N
• hipred_score: 0.327
• ghis: 0.466

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.975

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Hist2h4