TFRC

transferrin receptor, the group of M28 metallopeptidases|CD molecules

Basic information

Region (hg38): 3:196012511-196082153

Links

ENSG00000072274 ∙ NCBI:7037 ∙ OMIM:190010 ∙ HGNC:11763 ∙ Uniprot:P02786 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• TFRC-related combined immunodeficiency (Supportive), mode of inheritance: AR
• TFRC-related combined immunodeficiency (Limited), mode of inheritance: Unknown
• TFRC-related combined immunodeficiency (Moderate), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Immunodeficiency 46	AR	Allergy/Immunology/Infectious	The condition has been described as involving severe childhood-onset infections, and and awareness may allow preventive measures, and early and aggressive treatment of infections; HSCT has been described	Allergy/Immunology/Infectious; Hematologic	26642240

ClinVar

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

• TFRC-related combined immunodeficiency (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TFRC 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			2	108	10	120
missense		1	205	4	3	213
nonsense						0
start loss						0
frameshift			1			1
inframe indel			1			1
splice donor/acceptor (+/-2bp)	1		1			2
splice region			9	21	3	33
non coding			2	106	47	155
Total	1	1	212	218	60

Highest pathogenic variant AF is 0.00000816

Variants in TFRC

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

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

Position	Type	Phenotype	Significance	ClinVar
3-196048004-G-GGAAAAA			Uncertain significance (-)
3-196051948-C-T			Likely benign (Jun 24, 2023)
3-196051957-A-C			Uncertain significance (Jun 02, 2023)
3-196051968-C-T			Uncertain significance (Dec 11, 2023)
3-196051978-G-C			Likely benign (Dec 21, 2023)
3-196052010-T-C			Uncertain significance (Jan 20, 2024)
3-196052014-T-C			Likely benign (Sep 05, 2023)
3-196052016-G-C			Uncertain significance (Feb 05, 2023)
3-196052027-T-C			Uncertain significance (Dec 21, 2023)
3-196052032-G-C		Inborn genetic diseases	Conflicting classifications of pathogenicity (Jan 25, 2024)
3-196052039-G-A		TFRC-related combined immunodeficiency	Uncertain significance (Jan 19, 2024)
3-196052040-T-C			Uncertain significance (Feb 02, 2022)
3-196052055-C-T			Uncertain significance (Aug 29, 2023)
3-196052056-G-A			Likely benign (Aug 16, 2022)
3-196052055-C-CGTG			Uncertain significance (Jul 17, 2023)
3-196052060-T-C			Uncertain significance (Jun 20, 2022)
3-196052069-C-T			Uncertain significance (Jan 13, 2024)
3-196052070-G-A		Inborn genetic diseases	Uncertain significance (Nov 07, 2022)
3-196052074-T-C			Likely benign (Nov 08, 2022)
3-196052077-C-T			Likely benign (Nov 27, 2023)
3-196052079-A-T		Inborn genetic diseases	Uncertain significance (May 13, 2024)
3-196052094-C-T			Uncertain significance (Mar 02, 2023)
3-196052101-C-T			Benign (Jan 31, 2024)
3-196052102-G-A		Hereditary breast ovarian cancer syndrome	Uncertain significance (Aug 01, 2020)
3-196052110-G-T			Likely benign (Dec 11, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TFRC	protein_coding	protein_coding	ENST00000360110	18	55007

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0000699	1.00	125732	0	16	125748	0.0000636

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.605	380	415	0.916	0.0000220	4992
Missense in Polyphen		131	162.63	0.80549		1941
Synonymous	-0.00406	155	155	1.00	0.00000877	1453
Loss of Function	3.58	14	37.7	0.371	0.00000178	492

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000208	0.000207
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.0000794	0.0000791
Middle Eastern	0.0000544	0.0000544
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Cellular uptake of iron occurs via receptor-mediated endocytosis of ligand-occupied transferrin receptor into specialized endosomes. Endosomal acidification leads to iron release. The apotransferrin-receptor complex is then recycled to the cell surface with a return to neutral pH and the concomitant loss of affinity of apotransferrin for its receptor. Transferrin receptor is necessary for development of erythrocytes and the nervous system (By similarity). A second ligand, the heditary hemochromatosis protein HFE, competes for binding with transferrin for an overlapping C-terminal binding site. Positively regulates T and B cell proliferation through iron uptake (PubMed:26642240). {ECO:0000250, ECO:0000269|PubMed:26642240, ECO:0000269|PubMed:3568132}.
• Disease: DISEASE: Immunodeficiency 46 (IMD46) [MIM:616740]: An autosomal recessive primary immunodeficiency disorder characterized by early-onset chronic diarrhea, recurrent infections, hypo- or agammaglobulinemia, normal lymphocyte counts, intermittent neutropenia, and intermittent thrombocytopenia. {ECO:0000269|PubMed:26642240}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: HIF-1 signaling pathway - Homo sapiens (human);Endocytosis - Homo sapiens (human);Phagosome - Homo sapiens (human);Hematopoietic cell lineage - Homo sapiens (human);Ferroptosis - Homo sapiens (human);Iron metabolism in placenta;Golgi Associated Vesicle Biogenesis;Clathrin derived vesicle budding;trans-Golgi Network Vesicle Budding;Vesicle-mediated transport;Transferrin endocytosis and recycling;Membrane Trafficking;TCR;Fibroblast growth factor-1;Transport of small molecules;Clathrin-mediated endocytosis;EGFR1;Cargo recognition for clathrin-mediated endocytosis;Iron uptake and transport;Validated targets of C-MYC transcriptional activation;HIF-1-alpha transcription factor network;FOXA2 and FOXA3 transcription factor networks (Consensus)

Recessive Scores

• pRec: 0.799

Intolerance Scores

• loftool: 0.531
• rvis_EVS: -0.71
• rvis_percentile_EVS: 14.67

Haploinsufficiency Scores

• pHI: 0.451
• hipred: Y
• hipred_score: 0.742
• ghis: 0.696

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.883

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Tfrc
• Phenotype: homeostasis/metabolism phenotype; cellular phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); liver/biliary system phenotype; immune system phenotype; digestive/alimentary 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); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system 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); embryo phenotype

Zebrafish Information Network

• Gene name: tfr1b
• Affected structure: post-vent region
• Phenotype tag: abnormal
• Phenotype quality: curved ventral

Gene ontology

• Biological process: regulation of cell growth;iron ion transport;cellular iron ion homeostasis;osteoclast differentiation;positive regulation of B cell proliferation;receptor internalization;transferrin transport;cellular response to drug;positive regulation of T cell proliferation;regulation of cell population proliferation;positive regulation of bone resorption;positive regulation of isotype switching;viral entry into host cell;membrane organization;cellular response to leukemia inhibitory factor
• Cellular component: extracellular region;extracellular space;endosome;early endosome;plasma membrane;integral component of plasma membrane;clathrin-coated pit;external side of plasma membrane;cell surface;endosome membrane;membrane;basolateral plasma membrane;clathrin-coated vesicle membrane;cytoplasmic vesicle;melanosome;perinuclear region of cytoplasm;recycling endosome;extracellular exosome;blood microparticle;extracellular vesicle;HFE-transferrin receptor complex
• Molecular function: virus receptor activity;RNA binding;double-stranded RNA binding;transferrin receptor activity;protein binding;transferrin transmembrane transporter activity;identical protein binding;protein homodimerization activity