MACROH2A1
protein-codingmacroH2A.1 histone, the group of H2A histones|Macro domain containing
Gene summary
Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Nucleosomes consist of approximately 146 bp of DNA wrapped around a histone octamer composed of pairs of each of the four core histones (H2A, H2B, H3, and H4). The chromatin fiber is further compacted through the interaction of a linker histone, H1, with the DNA between the nucleosomes to form higher order chromatin structures. This gene encodes a replication-independent histone that is a member of the histone H2A family. It replaces conventional H2A histones in a subset of nucleosomes where it represses transcription and participates in stable X chromosome inactivation. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2015]
- H2AFY
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~65.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0008520
Submitter: Orphanet
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to MACROH2A1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_138610.3. 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 | 1 | 3 | 4 | |||
| missense | 1 | 25 | 26 | |||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 4 | 4 | ||||
| Total | 0 | 1 | 30 | 0 | 3 | 34 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_613258.2 | 8 | MANE Select | |
| Ensembl | ENSP00000423563.1 | 8 | MANE Select | |
| RefSeq | NP_001035248.1 | 8 | Standard | |
| RefSeq | NP_001387330.1 | 8 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Systemic lupus erythematosus - Homo sapiens (human)
- Necroptosis - Homo sapiens (human)
- Alcoholism - Homo sapiens (human)
- H19 action Rb-E2F1 signaling and CDK-β-catenin activity
- ATF-2 transcription factor network
Biological Process
- negative regulation of transcription by RNA polymerase II
- chromatin organization
- nucleosome assembly
- dosage compensation
- regulation of lipid metabolic process
Molecular Function
- rDNA binding
- RNA polymerase II regulatory region sequence-specific DNA binding
- RNA polymerase II core promoter sequence-specific DNA binding
- DNA binding
- protein binding
Cellular Component
- nuclear chromosome
- nuclear chromosome, telomeric region
- nucleosome
- nuclear chromatin
- condensed chromosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000511689
- Coding exons
- 8
- Length
- 66015
- Individuals with no LoFs
- 125712
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 2
- Defined
- 125714
- p
- 0.00000795
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.30 | 84 | 223 | 0.377 | 0.0000132 | 2417 |
| Missense (PolyPhen) | 12 | 95.541 | 0.1256 | 1013 | ||
| Synonymous | 0.650 | 87 | 95.1 | 0.915 | 0.00000634 | 764 |
| Loss of Function | 2.85 | 2 | 13.1 | 0.152 | 5.53e-7 | 193 |
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 | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.0000089 | 0.0000088 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Variant histone H2A which replaces conventional H2A in a subset of nucleosomes where it represses transcription (PubMed:12718888, PubMed:15621527, PubMed:16428466). 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. Involved in stable X chromosome inactivation (PubMed:15897469). Inhibits the binding of transcription factors, including NF-kappa-B, and interferes with the activity of remodeling SWI/SNF complexes (PubMed:12718888, PubMed:16428466). Inhibits histone acetylation by EP300 and recruits class I HDACs, which induces a hypoacetylated state of chromatin (PubMed:16428466, PubMed:16107708). {ECO:0000269|PubMed:12718888, ECO:0000269|PubMed:15621527, ECO:0000269|PubMed:15897469, ECO:0000269|PubMed:16107708, ECO:0000269|PubMed:16428466}.; FUNCTION: Isoform 2: Represses SOD3 gene expression. {ECO:0000269|PubMed:23022728}.;
Recessive Scores
- pRec
- 0.212
Intolerance Scores
- LoFtool
- 0.137
- RVIS EVS
- -0.41
- RVIS percentile EVS
- 26.23
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.939
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Low | Low | Low |
| Primary Immunodeficiency | Low | Low | Low |
| Cancer | Low | Low | Low |