H1-4
protein-codingH1.4 linker histone, cluster member, the group of H1 histones
Gene summary
Histones are basic nuclear proteins responsible for 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 H1 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]
- H1F4
- HIST1H1E
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~0.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0000508
Submitter: ClinGen
Variants in *H1-4* were first reported in relation to syndromic intellectual disability (also known as Rahman syndrome) in 2017 (Tatton-Brown et al., PMID: 28475857). Affected individuals present with mild to severe intellectual disability associated with a distinctive facial appearance. Other clinical features include hypotonia, behavioral issues (including autism spectrum disorder or autistic features), cryptorchidism, brain MRI abnormalities, abnormal dentition, cardiac anomalies, skeletal anomalies, and hypothyroidism (PMID: 31400068). Increased growth, reported in the initial description, was not observed in larger cohorts, although macrocephaly is common (PMID: 31447100). Numerous unique frameshift variants in the C-terminal domain of *H1-4* have been reported, with all of the variants occurring *de novo*. This curation includes variants in 8 probands in 4 publications (PMIDs: 2847585, 2938384, 33086257, 34788807). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. *H1-4* encodes histone H1.4, a member of the linker histone family that contributes to higher-order chromatin folding. This gene-disease relationship is supported by functional alterations in both patient and non-patient cells (PMIDs: 31447100, 34788807). The C-terminal frameshift variants result in stable truncated proteins that disrupt chromatin condensation and are associated with a specific methylation pattern (PMID: 31447100). The mechanism of disease has been postulated to be a dominant negative effect or gain of function (PMIDs: 31447100, 34788807). In summary, there is definitive evidence supporting the relationship between *H1-4* and syndromic intellectual disability. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on May 3, 2023 (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0044323
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0044323
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0044323
Submitter: Illumina
Inheritance Pattern: AD
Disease ID:MONDO:0044323
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0044323
Submitter: PanelApp Australia
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 H1-4 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005321.3. 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 | 55 | 2 | 57 | |||
| missense | 2 | 92 | 59 | 153 | ||
| nonsense | 0 | |||||
| start loss | 1 | 1 | ||||
| frameshift | 25 | 16 | 15 | 56 | ||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 25 | 18 | 108 | 114 | 2 | 267 |
Highest pathogenic variant AF is 0.000004357103
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_005312.1 | 1 | MANE Select | |
| Ensembl | ENSP00000307705.4 | 1 | MANE Select |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Pathways Affected in Adenoid Cystic Carcinoma
- Formation of Senescence-Associated Heterochromatin Foci (SAHF)
- DNA Damage/Telomere Stress Induced Senescence
- Cellular Senescence
- Cellular responses to stress
Biological Process
- negative regulation of transcription by RNA polymerase II
- nucleosome assembly
- regulation of transcription, DNA-templated
- nucleosome positioning
- chromosome condensation
Molecular Function
- double-stranded DNA binding
- RNA binding
- calcium ion binding
- protein binding
- ATP binding
Cellular Component
- nuclear nucleosome
- nucleus
- nuclear heterochromatin
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000304218
- Coding exons
- 1
- Length
- 785
- 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 | -6.72 | 340 | 127 | 2.68 | 0.00000551 | 1373 |
| Missense (PolyPhen) | 27 | 23.319 | 1.1578 | 276 | ||
| Synonymous | -16.8 | 217 | 56.6 | 3.83 | 0.00000264 | 482 |
| Loss of Function | 0.913 | 1 | 2.58 | 0.387 | 9.94e-8 | 67 |
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:
- Function
- FUNCTION: Histone H1 protein binds to linker DNA between nucleosomes forming the macromolecular structure known as the chromatin fiber. Histones H1 are necessary for the condensation of nucleosome chains into higher-order structured fibers. Acts also as a regulator of individual gene transcription through chromatin remodeling, nucleosome spacing and DNA methylation (By similarity). {ECO:0000250}.;
- Disease
- DISEASE: Rahman syndrome (RMNS) [MIM:617537]: An autosomal dominant syndrome characterized by intellectual disability and overgrowth manifesting as increased birth length, height, weight, and/or head circumference. {ECO:0000269|PubMed:28475857}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.228
Intolerance Scores
- LoFtool
- 0.421
- RVIS EVS
- -1.2
- RVIS percentile EVS
- 5.83
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- 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 |