HCFC1
protein-codinghost cell factor C1, the group of NSL histone acetyltransferase complex|Protein phosphatase 1 regulatory subunits|ATAC complex
Gene summary
This gene is a member of the host cell factor family and encodes a protein with five Kelch repeats, a fibronectin-like motif, and six HCF repeats, each of which contains a highly specific cleavage signal. This nuclear coactivator is proteolytically cleaved at one of the six possible sites, resulting in the creation of an N-terminal chain and the corresponding C-terminal chain. The final form of this protein consists of noncovalently bound N- and C-terminal chains. The protein is involved in control of the cell cycle and transcriptional regulation during herpes simplex virus infection. Alternatively spliced variants which encode different protein isoforms have been described; however, not all variants have been fully characterized. [provided by RefSeq, Jul 2008]
- HFC1
- MRX3
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~24.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: XL
Disease ID:MONDO:0010657
Submitter: G2P
Inheritance Pattern: XL
Disease ID:MONDO:0100284
Submitter: Illumina
Inheritance Pattern: XL
Disease ID:MONDO:0019181
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010657
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010657
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: XL
Disease ID:MONDO:0100284
Submitter: ClinGen
The HCFC1 gene is located on chromosome Xq28 and encodes the host cell-factor 1, a transcriptional co-regulator protein implicated in the control of the cell cycle. HCFC1 was first reported in relation to X-linked intellectual disability (ID) in 2012 (PMID: 23000143). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Cases from twenty-one families were curated; most of the identified HCFC1 variants are missense changes, with 9 missense variants, one 5’UTR variant, and one splice variant resulting in an in-frame exonic deletion reported (PMIDs: 23000143, 24011988, 25740848, 26893841, 28363510, and 33517344). Most individuals inherited the HCFC1 variant from an unaffected mother, with only one de novo case scored. Most reported cases were males but mildly affected females have been described in one family with a splice variant (PMID: 33517344). Affected males present with either methylmalonic acidemia and hyperhomocysteinemia, type cblX, a severe metabolic disorder associated with ID; or with ID with mild or absent metabolic abnormalities. There is a tentative genotype-phenotype correlation in which the metabolic form is associated with HCFC1 missense variants in the conserved kelch domain and the non-metabolic phenotype is associated with HCFC1 variants outside the kelch domain, in domains important for protein interactions, heterodimerization, and nuclear localization (PMID: 33517344). This gene-disease association is supported by functional alteration in both non-patient and patient cells, demonstrating that HCFC1 binds to the MMACHC promoter, which may underlie the metabolic phenotype in severely affected patients (PMIDs: 24011988, 25281006). A zebrafish knockdown model results in craniofacial defects that can be rescued by co-injection of human HCFC1 or MMACHC (PMID: 25281006). Conditional knockout of HCFC1 in the ventral telencephalon in mouse showed reduced Nkx2.1-derived neurons and glia due to increased cell death, defects of the anterior commissure and corpus callosum, and alteration in cortical lamination (PMID: 31207118). In summary, HCFC1 is definitively associated with X-linked ID. This has been repeatedly demonstrated in both research and clinical diagnostic settings, and has been upheld over time. Please note, due to a known issue in which the Gene Curation Interface is capping the total number of points allotted for missense variants at 7 points (not yet reflective of the change in scoring in SOP version 8), the total number of points for genetic evidence is not reflecting the true amount, which is the maximum of 12 points. This curation was approved by the ID/Autism Gene Curation Expert Panel on 3/17/21 (SOP Version 8).
Inheritance Pattern: XL
Disease ID:MONDO:0010657
Submitter: PanelApp Australia
Inheritance Pattern: XL
Disease ID:MONDO:0010657
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Neurologic
Intervention: Biochemical
Rationale: Medical interventions (eg, cofactor therapy with injectable hydroxycobalamin) and dietary management (eg, high-calorie, low protein diet and avoidance of fasting, with measures taken to avoid/treat decompensation) may be to beneficial in both acute and chronic states
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to HCFC1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005334.3. 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 | 49 | 549 | 112 | 710 | ||
| missense | 5 | 6 | 502 | 120 | 10 | 643 |
| nonsense | 12 | 12 | ||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 43 | 44 | |||
| Total | 6 | 7 | 606 | 669 | 122 | 1410 |
Highest pathogenic variant AF is 0.0000019222489
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_005325.2 | 26 | MANE Select | |
| Ensembl | ENSP00000309555.7 | 26 | MANE Select | |
| RefSeq | NP_001397634.1 | 26 | Standard | |
| RefSeq | NP_001427772.1 | 26 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| hcfc1b | Danio rerio | Structure: neuronal stem cell Quality: disrupted abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Herpes simplex infection - Homo sapiens (human)
- Mitochondrial Gene Expression
- Post-translational protein modification
- Metabolism of proteins
- Chromatin modifying enzymes
Biological Process
- negative regulation of transcription by RNA polymerase II
- blastocyst hatching
- regulation of transcription, DNA-templated
- mitochondrion organization
- cell cycle
Molecular Function
- DNA-binding transcription activator activity, RNA polymerase II-specific
- chromatin binding
- transcription coactivator activity
- protein binding
- protein binding, bridging
Cellular Component
- histone acetyltransferase complex
- nucleus
- nucleoplasm
- Ada2/Gcn5/Ada3 transcription activator complex
- cytoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000310441
- Coding exons
- 26
- Length
- 24255
- 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 | 5.63 | 419 | 893 | 0.469 | 0.0000774 | 12925 |
| Missense (PolyPhen) | 218 | 598.05 | 0.36452 | 8637 | ||
| Synonymous | -2.08 | 477 | 423 | 1.13 | 0.0000421 | 4642 |
| Loss of Function | 6.50 | 0 | 49.2 | 0.00 | 0.00000349 | 769 |
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: Involved in control of the cell cycle (PubMed:10629049, PubMed:10779346, PubMed:15190068, PubMed:16624878, PubMed:23629655). Also antagonizes transactivation by ZBTB17 and GABP2; represses ZBTB17 activation of the p15(INK4b) promoter and inhibits its ability to recruit p300 (PubMed:10675337, PubMed:12244100). Coactivator for EGR2 and GABP2 (PubMed:12244100, PubMed:14532282). Tethers the chromatin modifying Set1/Ash2 histone H3 'Lys-4' methyltransferase (H3K4me) and Sin3 histone deacetylase (HDAC) complexes (involved in the activation and repression of transcription, respectively) together (PubMed:12670868). Component of a THAP1/THAP3-HCFC1-OGT complex that is required for the regulation of the transcriptional activity of RRM1 (PubMed:20200153). As part of the NSL complex it may be involved in acetylation of nucleosomal histone H4 on several lysine residues (PubMed:20018852). Recruits KMT2E/MLL5 to E2F1 responsive promoters promoting transcriptional activation and thereby facilitates G1 to S phase transition (PubMed:23629655). {ECO:0000269|PubMed:10629049, ECO:0000269|PubMed:10675337, ECO:0000269|PubMed:10779346, ECO:0000269|PubMed:12244100, ECO:0000269|PubMed:12670868, ECO:0000269|PubMed:14532282, ECO:0000269|PubMed:15190068, ECO:0000269|PubMed:16624878, ECO:0000269|PubMed:20018852, ECO:0000269|PubMed:20200153, ECO:0000269|PubMed:23629655}.;
- Disease
- DISEASE: Mental retardation, X-linked 3 (MRX3) [MIM:309541]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non- syndromic X-linked mental retardation, while syndromic mental retardation presents with associated physical, neurological and/or psychiatric manifestations. {ECO:0000269|PubMed:23000143}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.158
Intolerance Scores
- LoFtool
- 0.00303
- RVIS EVS
- -1.46
- RVIS percentile EVS
- 3.86
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.833
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |