TFRC

protein-coding

transferrin receptor, the group of M28 metallopeptidases|CD molecules

Gene summary

This gene encodes a cell surface receptor necessary for cellular iron uptake by the process of receptor-mediated endocytosis. This receptor is required for erythropoiesis and neurologic development. Multiple alternatively spliced variants have been identified. [provided by RefSeq, Sep 2015]

MANE transcript

NM_001128148.3

Inheritance

ClinVar variants

P:2U:313B:166

Top phenotype

Immunodeficiency 46

gnomAD constraint

pLI —, LoF o/e 0.37

Max pathogenic AF

—

Genomic locus

chr3:196,012,511-196,082,153

External References & Databases

Ensembl (ENSG00000072274)

Transcript & Mutation Effects

hg38 • Region Span ~69.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

TFRC-related combined immunodeficiencyLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0014760

Submitter: Labcorp Genetics (formerly Invitae)

TFRC-related combined immunodeficiencyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014760

Submitter: PanelApp Australia

TFRC-related combined immunodeficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014760

Submitter: ClinGen

TFRC was first reported in relation to autosomal recessive TFRC-related combined immunodeficiency in 2016 (Jabara et al., 26642240). Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Two missense variants have been reported in eight probands, in three publications (PMID 26642240, 32851577, 38270687). This variant segregated with disease in eight additional family members. Symptoms include recurrent sinopulmonary infections, chronic diarrhea, recurrent epistaxis secondary to thrombocytopenia, mild anemia, and immunodeficiency. Heterozygous carriers were reported to be unaffected. This gene-disease relationship is supported by murine models, functional alteration and rescue experiments in patient cells, in vitro assays showing the gene product performs a biochemical function consistent with the phenotype, and functional alteration in non-patient cells (PMID: 3568132, 6265934, 10192390, 26642240). Patient cells homozygous for the Y20H variant showed defective transferrin uptake and transduction of wild type TfR1 corrected defective transferrin uptake (PMID 26642240). TFRC null mice are embryonic lethal while Tfrc Y20H/Y20H mice had significantly decreased serum IgG, hemoglobin, and MCV compared to controls, as well as impaired receptor internalization on T and B cells (PMID: 26642240, 10192390). In summary, there is definitive evidence to support the relationship between TFRC and autosomal recessive TFRC-related combined immunodeficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the SCID-CID GCEP on October 13, 2022. It was re-evaluated on March 20, 2025. As a result of this reevaluation, the classification increased from Moderate to Definitive with the addition of a new case (PMIDs: 38270687).

TFRC-related combined immunodeficiencyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014760

Submitter: G2P

TFRC-related combined immunodeficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014760

Submitter: Orphanet

Clinical Genomic Database (CGD)

Immunodeficiency 46AR

Manifestation: Allergy/Immunology/Infectious; Hematologic

Intervention: Allergy/Immunology/Infectious

Rationale: 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

Refs: 26642240

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TFRC variants in ClinVar

7 Conditions Cataloged

not providedTotal: 631

Inborn genetic diseasesTotal: 63

not specifiedTotal: 19

TFRC-related combined immunodeficiencyTotal: 10

TFRC-related disorderTotal: 10

Combined immunodeficiencyTotal: 1

Hereditary breast ovarian cancer syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001128148.3. 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			6 clinvar	148 clinvar	5 clinvar	159
missense		1 clinvar	297 clinvar	12 clinvar	1 clinvar	311
nonsense						0
start loss						0
frameshift			5 clinvar			5
splice donor/acceptor (+/-2bp)	1 clinvar		5 clinvar			6
Total	1	1	313	160	6	481

Highest pathogenic variant AF is 0.0003295038

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 55 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001128148.3	RefSeq	NP_001121620.1	18	MANE Select
ENST00000360110.9	Ensembl	ENSP00000353224.4	18	MANE Select
NM_001313965.2	RefSeq	NP_001300894.1	16	Standard
NM_001313966.2	RefSeq	NP_001300895.1	12	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
tfr1b	Danio rerio	Structure: post-vent region Quality: curved ventral abnormal

Gene / Model

Organism

Observed Phenotype

tfr1b

Danio rerio

Structure: post-vent region

Quality: curved ventral

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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)

Biological Process

regulation of cell growth
iron ion transport
cellular iron ion homeostasis
osteoclast differentiation
positive regulation of B cell proliferation

Molecular Function

virus receptor activity
RNA binding
double-stranded RNA binding
transferrin receptor activity
protein binding

Cellular Component

extracellular region
extracellular space
endosome
early endosome
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000360110
Coding exons: 18
Length: 55007
Individuals with no LoFs: 125732
Homozygous LoFs: 0
Heterozygous LoFs: 16
Defined: 125748
p: 0.0000636

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.605	380	415	0.916	0.0000220	4992
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000063	0.000062	rare
Latino/Admixed American	0.00015	0.00014	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000079	0.000079	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec: 0.799

Intolerance Scores

LoFtool: 0.531
RVIS EVS: -0.71
RVIS percentile EVS: 14.67

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.883

Gene Damage Prediction

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