HFE

homeostatic iron regulator, the group of C1-set domain containing

Basic information

Region (hg38): 6:26087280-26098343

Links

ENSG00000010704 ∙ NCBI:3077 ∙ OMIM:613609 ∙ HGNC:4886 ∙ Uniprot:Q30201 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hemochromatosis type 1 (Strong), mode of inheritance: AR
• hemochromatosis type 1 (Supportive), mode of inheritance: AR
• hemochromatosis type 1 (Definitive), mode of inheritance: AR
• hemochromatosis type 1 (Definitive), mode of inheritance: AR
• hemochromatosis type 1 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hemochromatosis	AR/Digenic	Biochemical; Gastrointestinal; Hematologic	Interventions such as phlebotomy (including when presymptomatic) and dietary measures may be effective, though there is some controversy regarding specifics	Biochemical; Cardiovascular; Endocrine; Gastrointestinal; Hematologic	678784; 3979748; 4058506; 3658574; 2919850; 2346731; 1614776; 8419246; 8051482; 8943161; 8696333; 9132598; 9867745; 9867746; 9792863; 9687253; 11336458; 10401000; 10471457; 11069625; 11087882; 10673305; 10673304; 11260010; 11386022; 11423500; 11325323; 11565552; 12915468; 14618419; 15024747; 15347835; 15175440; 15466004; 15657376; 18061062; 18566337; 18809761; 19214511; 20843714; 21901659; 21411349; 22265917; 22196777; 20301613
Heterozygotes may display mild manifestations in some circumstances; Digenic inheritance (with HAMP) has been described

ClinVar

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

• Hereditary hemochromatosis (148 variants)
• Hemochromatosis type 1 (65 variants)
• not provided (47 variants)
• not specified (14 variants)
• Inborn genetic diseases (13 variants)
• 6 conditions (12 variants)
• Cardiomyopathy (2 variants)
• Bronze diabetes (2 variants)
• HFE POLYMORPHISM (2 variants)
• Cutaneous photosensitivity;Porphyrinuria (1 variants)
• Abnormality of iron homeostasis (1 variants)
• HFE-related condition (1 variants)
• 7 conditions (1 variants)
• Alzheimer disease type 1 (1 variants)
• Hereditary cancer-predisposing syndrome (1 variants)
• Cystic fibrosis (1 variants)
• Variegate porphyria (1 variants)
• HFE-related disorder (1 variants)
• Juvenile hemochromatosis (1 variants)
• HFE INTRONIC POLYMORPHISM (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the HFE 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				72	1	73
missense	1	1	51	2		55
nonsense	8	1				9
start loss						0
frameshift	6	1	2			9
inframe indel		1				1
splice donor/acceptor (+/-2bp)	1	6				7
splice region			1	9		10
non coding			27	14	7	48
Total	16	10	80	88	8

Highest pathogenic variant AF is 0.0000329

Variants in HFE

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

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

Position	Type	Phenotype	Significance	ClinVar
6-26087345-G-C		Hemochromatosis type 1	Uncertain significance (Jan 12, 2018)
6-26087393-C-G		Hemochromatosis type 1	Benign (Apr 27, 2017)
6-26087421-G-A			Uncertain significance (Apr 29, 2021)
6-26087434-T-C		Hemochromatosis type 1 • Hereditary hemochromatosis	Conflicting classifications of pathogenicity (Nov 24, 2022)
6-26087437-G-A			Uncertain significance (Apr 11, 2022)
6-26087446-C-T		Hereditary hemochromatosis	Likely benign (Oct 17, 2023)
6-26087457-G-C		HFE-related disorder	Uncertain significance (Nov 13, 2023)
6-26087458-G-C		Hemochromatosis type 1 • Hereditary hemochromatosis • 6 conditions	Uncertain significance (Aug 01, 2023)
6-26087460-C-G			Uncertain significance (Jul 09, 2019)
6-26087461-G-A		Hereditary hemochromatosis • Hemochromatosis type 1 • HFE-related disorder	Conflicting classifications of pathogenicity (Feb 01, 2024)
6-26087463-C-T		Hereditary hemochromatosis	Uncertain significance (Sep 22, 2022)
6-26087464-G-C		Hereditary hemochromatosis	Likely benign (Dec 02, 2021)
6-26087476-G-C		Hereditary hemochromatosis	Likely benign (Jul 03, 2022)
6-26087480-C-G		Hemochromatosis type 1 • Hereditary hemochromatosis	Uncertain significance (Feb 08, 2023)
6-26087483-T-C		Hereditary hemochromatosis	Likely benign (Aug 25, 2022)
6-26087490-C-T		Hereditary hemochromatosis • Hemochromatosis type 1	Uncertain significance (Feb 08, 2023)
6-26087491-C-T		Hereditary hemochromatosis	Likely benign (Nov 13, 2023)
6-26087494-G-A		Hereditary hemochromatosis	Likely benign (Aug 23, 2023)
6-26087494-G-C		Hereditary hemochromatosis	Likely benign (Apr 28, 2023)
6-26087497-C-T		Hereditary hemochromatosis	Likely benign (Sep 03, 2019)
6-26087508-G-A		Hereditary hemochromatosis • Hemochromatosis type 1	Conflicting classifications of pathogenicity (Jan 29, 2024)
6-26087518-T-C		Alzheimer disease type 1 • Hereditary hemochromatosis	Likely pathogenic (Feb 03, 2023)
6-26087524-C-A		Hereditary hemochromatosis	Likely benign (Jun 17, 2022)
6-26087524-C-T		Hereditary hemochromatosis	Likely benign (Sep 16, 2020)
6-26087525-G-T		Hereditary hemochromatosis	Likely benign (Nov 11, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
HFE	protein_coding	protein_coding	ENST00000357618	6	11063

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
2.56e-8	0.488	125698	0	49	125747	0.000195

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.633	165	190	0.871	0.0000105	2263
Missense in Polyphen		61	68.531	0.8901		882
Synonymous	0.757	67	75.4	0.889	0.00000420	680
Loss of Function	0.961	14	18.5	0.759	9.01e-7	190

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000260	0.000260
Ashkenazi Jewish	0.00	0.00
East Asian	0.00131	0.00131
Finnish	0.00	0.00
European (Non-Finnish)	0.000106	0.000105
Middle Eastern	0.00131	0.00131
South Asian	0.000131	0.000131
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Binds to transferrin receptor (TFR) and reduces its affinity for iron-loaded transferrin. {ECO:0000269|PubMed:9465039}.
• Disease: DISEASE: Hemochromatosis 1 (HFE1) [MIM:235200]: A disorder of iron metabolism characterized by iron overload. Excess iron is deposited in a variety of organs leading to their failure, and resulting in serious illnesses including cirrhosis, hepatomas, diabetes, cardiomyopathy, arthritis, and hypogonadotropic hypogonadism. Severe effects of the disease usually do not appear until after decades of progressive iron loading. {ECO:0000269|PubMed:10094552, ECO:0000269|PubMed:10194428, ECO:0000269|PubMed:10401000, ECO:0000269|PubMed:10575540, ECO:0000269|PubMed:11423500, ECO:0000269|PubMed:11446670, ECO:0000269|PubMed:12542741, ECO:0000269|PubMed:12584229, ECO:0000269|PubMed:12737937, ECO:0000269|PubMed:14633868, ECO:0000269|PubMed:15046077, ECO:0000269|PubMed:15965644, ECO:0000269|PubMed:18157833, ECO:0000269|PubMed:8696333, ECO:0000269|PubMed:9024376, ECO:0000269|PubMed:9106528, ECO:0000269|PubMed:9620340, ECO:0000269|Ref.25}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Variegate porphyria (VP) [MIM:176200]: A form of porphyria. Porphyrias are inherited defects in the biosynthesis of heme, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. They are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in red blood cells or in the liver. Variegate porphyria is the most common form of porphyria in South Africa. It is characterized by skin hyperpigmentation and hypertrichosis, abdominal pain, tachycardia, hypertension and neuromuscular disturbances. High fecal levels of protoporphyrin and coproporphyrin, increased urine uroporphyrins and iron overload are typical markers of the disease. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Iron overload due to HFE variants is a precipitating or exacerbating factor in variegate porphyria.; DISEASE: Microvascular complications of diabetes 7 (MVCD7) [MIM:612635]: Pathological conditions that develop in numerous tissues and organs as a consequence of diabetes mellitus. They include diabetic retinopathy, diabetic nephropathy leading to end- stage renal disease, and diabetic neuropathy. Diabetic retinopathy remains the major cause of new-onset blindness among diabetic adults. It is characterized by vascular permeability and increased tissue ischemia and angiogenesis. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.
• Pathway: Hfe effect on hepcidin production;Transferrin endocytosis and recycling;Transport of small molecules;Iron uptake and transport (Consensus)

Recessive Scores

• pRec: 0.730

Intolerance Scores

• loftool: 0.406
• rvis_EVS: 0.08
• rvis_percentile_EVS: 60.31

Haploinsufficiency Scores

• pHI: 0.107
• hipred: N
• hipred_score: 0.147
• ghis: 0.556

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.826

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Hfe
• Phenotype: normal 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); hematopoietic system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary system phenotype; immune system phenotype; skeleton phenotype; limbs/digits/tail phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); digestive/alimentary phenotype; growth/size/body region phenotype; cellular phenotype; homeostasis/metabolism phenotype

Gene ontology

• Biological process: antigen processing and presentation of peptide antigen via MHC class I;negative regulation of T cell antigen processing and presentation;negative regulation of T cell cytokine production;cellular iron ion homeostasis;acute-phase response;female pregnancy;response to iron ion;cellular response to iron ion starvation;positive regulation of gene expression;positive regulation of pathway-restricted SMAD protein phosphorylation;antigen processing and presentation;BMP signaling pathway;positive regulation of protein binding;negative regulation of proteasomal ubiquitin-dependent protein catabolic process;transferrin transport;regulation of iron ion transport;hormone biosynthetic process;positive regulation of receptor-mediated endocytosis;iron ion homeostasis;multicellular organismal iron ion homeostasis;protein-containing complex assembly;cellular response to iron ion;positive regulation of peptide hormone secretion;liver regeneration;iron ion import across plasma membrane;negative regulation of receptor binding;positive regulation of receptor binding;negative regulation of antigen processing and presentation of endogenous peptide antigen via MHC class I;positive regulation of ferrous iron binding;positive regulation of transferrin receptor binding;response to iron ion starvation;regulation of protein localization to cell surface;negative regulation of ubiquitin-dependent protein catabolic process;negative regulation of signaling receptor activity;positive regulation of signaling receptor activity;negative regulation of CD8-positive, alpha-beta T cell activation
• Cellular component: extracellular space;early endosome;plasma membrane;integral component of plasma membrane;external side of plasma membrane;cytoplasmic vesicle;MHC class I protein complex;apical part of cell;basal part of cell;perinuclear region of cytoplasm;recycling endosome;terminal web;HFE-transferrin receptor complex
• Molecular function: signaling receptor binding;protein binding;beta-2-microglobulin binding;co-receptor binding;peptide antigen binding;transferrin receptor binding