HCFC1

host cell factor C1, the group of NSL histone acetyltransferase complex|Protein phosphatase 1 regulatory subunits|ATAC complex

Basic information

Region (hg38): X:153947556-153971818

Previous symbols: [ "HFC1", "MRX3" ]

Links

ENSG00000172534 ∙ NCBI:3054 ∙ OMIM:300019 ∙ HGNC:4839 ∙ Uniprot:P51610 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• methylmalonic acidemia with homocystinuria, type cblX (Definitive), mode of inheritance: XLR
• methylmalonic acidemia with homocystinuria, type cblX (Moderate), mode of inheritance: XL
• non-syndromic X-linked intellectual disability (Supportive), mode of inheritance: XL
• methylmalonic acidemia with homocystinuria, type cblX (Supportive), mode of inheritance: XL
• X-linked intellectual disability (Definitive), mode of inheritance: XL
• methylmalonic acidemia with homocystinuria, type cblX (Definitive), mode of inheritance: XL
• methylmalonic acidemia with homocystinuria, type cblX (Strong), mode of inheritance: XL
• X-linked intellectual disability (Definitive), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Methylmalonic aciduria and homocysteinemia, cblX type	XL	Biochemical	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	Biochemical; Neurologic	24011988

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the HCFC1 gene.

• Methylmalonic acidemia with homocystinuria, type cblX (536 variants)
• not provided (219 variants)
• not specified (124 variants)
• Inborn genetic diseases (47 variants)
• Disorders of Intracellular Cobalamin Metabolism (5 variants)
• HCFC1-related condition (3 variants)
• Intellectual disability (2 variants)
• X-linked intellectual disability (2 variants)
• Kabuki syndrome 1 (1 variants)
• Cobalamin C disease (1 variants)
• See cases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the HCFC1 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			10	235	62	307
missense	4	1	206	39	9	259
nonsense						0
start loss						0
frameshift						0
inframe indel			9	2	1	12
splice donor/acceptor (+/-2bp)		1	1			2
splice region			10	20	1	31
non coding			1	80	43	124
Total	4	2	227	356	115

Variants in HCFC1

This is a list of pathogenic ClinVar variants found in the HCFC1 region.

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

Position	Type	Phenotype	Significance	ClinVar
X-153949054-G-A			Benign (Aug 14, 2018)
X-153949297-C-T			Likely benign (May 25, 2021)
X-153949359-G-A		Methylmalonic acidemia with homocystinuria, type cblX	Benign (Oct 04, 2023)
X-153949361-C-T		Methylmalonic acidemia with homocystinuria, type cblX	Uncertain significance (Sep 04, 2022)
X-153949365-A-G		Methylmalonic acidemia with homocystinuria, type cblX	Likely benign (Nov 20, 2023)
X-153949366-G-C			Uncertain significance (Oct 01, 2021)
X-153949381-G-C			Uncertain significance (Feb 01, 2022)
X-153949386-C-A		Methylmalonic acidemia with homocystinuria, type cblX	Uncertain significance (Mar 17, 2021)
X-153949390-G-A			Likely benign (May 17, 2018)
X-153949391-G-A		Methylmalonic acidemia with homocystinuria, type cblX	Benign (Jan 22, 2024)
X-153949394-G-A		Methylmalonic acidemia with homocystinuria, type cblX	Benign (Dec 30, 2023)
X-153949402-A-G		Methylmalonic acidemia with homocystinuria, type cblX	Likely benign (Sep 15, 2023)
X-153949406-A-G		Methylmalonic acidemia with homocystinuria, type cblX	Benign (Jan 29, 2024)
X-153949533-G-A		Methylmalonic acidemia with homocystinuria, type cblX	Benign (Dec 14, 2023)
X-153949534-A-G		Methylmalonic acidemia with homocystinuria, type cblX	Likely benign (Mar 27, 2023)
X-153949538-G-C		Methylmalonic acidemia with homocystinuria, type cblX	Likely benign (Oct 17, 2023)
X-153949539-G-A		Methylmalonic acidemia with homocystinuria, type cblX	Likely benign (Jan 26, 2023)
X-153949540-G-C		Methylmalonic acidemia with homocystinuria, type cblX	Likely benign (Aug 14, 2021)
X-153949542-T-C		Methylmalonic acidemia with homocystinuria, type cblX	Likely benign (Jun 12, 2023)
X-153949553-A-G			Uncertain significance (Jan 20, 2023)
X-153949560-G-A			Uncertain significance (Dec 15, 2022)
X-153949570-G-A		Methylmalonic acidemia with homocystinuria, type cblX	Likely benign (Jan 24, 2023)
X-153949575-G-A			Pathogenic (Jul 01, 2021)
X-153949579-G-A		Methylmalonic acidemia with homocystinuria, type cblX	Conflicting classifications of pathogenicity (Nov 02, 2021)
X-153949582-G-C		Methylmalonic acidemia with homocystinuria, type cblX	Likely benign (May 28, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
HCFC1	protein_coding	protein_coding	ENST00000310441	26	24255

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	1.86e-8	0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	5.63	419	893	0.469	0.0000774	12925
Missense in 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

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: 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.
• Pathway: Herpes simplex infection - Homo sapiens (human);Mitochondrial Gene Expression;Post-translational protein modification;Metabolism of proteins;Chromatin modifying enzymes;HATs acetylate histones;UCH proteinases;Deubiquitination;Chromatin organization;Transcriptional activation of mitochondrial biogenesis;Mitochondrial biogenesis;Organelle biogenesis and maintenance (Consensus)

Recessive Scores

• pRec: 0.158

Intolerance Scores

• loftool: 0.00303
• rvis_EVS: -1.46
• rvis_percentile_EVS: 3.86

Haploinsufficiency Scores

• pHI: 0.358
• hipred: Y
• hipred_score: 0.831
• ghis: 0.560

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.833

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Hcfc1
• Phenotype: embryo phenotype; liver/biliary system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); growth/size/body region phenotype; cellular phenotype

Zebrafish Information Network

• Gene name: hcfc1b
• Affected structure: neuronal stem cell
• Phenotype tag: abnormal
• Phenotype quality: disrupted

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;blastocyst hatching;regulation of transcription, DNA-templated;mitochondrion organization;cell cycle;positive regulation of gene expression;protein deubiquitination;release from viral latency;regulation of protein complex assembly;histone H4-K5 acetylation;histone H4-K8 acetylation;histone H4-K16 acetylation;positive regulation of cell cycle;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;protein stabilization;cellular response to organic cyclic compound
• Cellular component: histone acetyltransferase complex;nucleus;nucleoplasm;Ada2/Gcn5/Ada3 transcription activator complex;cytoplasm;membrane;axon;dendrite;protein-containing complex;neuronal cell body;Set1C/COMPASS complex;SAGA-type complex;MLL1 complex
• Molecular function: DNA-binding transcription activator activity, RNA polymerase II-specific;chromatin binding;transcription coactivator activity;protein binding;protein binding, bridging;activating transcription factor binding;identical protein binding;histone acetyltransferase activity (H4-K5 specific);histone acetyltransferase activity (H4-K8 specific);cadherin binding;histone acetyltransferase activity (H4-K16 specific);sequence-specific double-stranded DNA binding