TFRC-related combined immunodeficiency

Summary

TFRC-related combined immunodeficiency (MONDO:0014760) is a disease caused by TFRC (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TFRC (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 18

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	TFRC-related combined immunodeficiency
Mondo ID	MONDO:0014760
OMIM	616740
Orphanet	476113
DOID	DOID:0111948
UMLS	C5568133
MedGen	1799556
GARD	0017849
Is cancer (heuristic)	no

Also known as: CID due to TFRC deficiency · IMD46 · immunodeficiency 46 · immunodeficiency type 46

Data availability: 18 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › immunodeficiency disease › TFRC-related combined immunodeficiency

Related subtypes (94): B cell deficiency, T-cell immunodeficiency, complement deficiency, myalgic encephalomeyelitis/chronic fatigue syndrome, hypoproteinemia, hypercatabolic, X-linked lymphoproliferative syndrome, Wiskott-Aldrich syndrome, autosomal dominant form, immunodeficiency due to CD25 deficiency, immunodeficiency 67, primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency, immunodeficiency 35, pyogenic bacterial infections due to MyD88 deficiency, lymphoproliferative syndrome 1, FADD-related immunodeficiency, immunodeficiency 31B, Wiskott-Aldrich syndrome 2, cryptosporidiosis-chronic cholangitis-liver disease syndrome, idiopathic CD4 lymphocytopenia, immunodeficiency 23, DOCK2 deficiency, immunodeficiency 45, combined immunodeficiency, autoimmune hemolytic anemia-autoimmune thrombocytopenia-primary immunodeficiency syndrome, immunodeficiency due to selective anti-polysaccharide antibody deficiency, immunodeficiency 57, immunodeficiency 14b, autosomal recessive, immunodeficiency 98 with autoinflammation, X-linked, immunodeficiency 102, immunodeficiency 74, COVID-19-related, X-linked, immunodeficiency 66, immunodeficiency 80 with or without congenital cardiomyopathy, immunodeficiency 81, immunodeficiency 82 with systemic inflammation, immunodeficiency 84, immunodeficiency 85 and autoimmunity, immunodeficiency 86, immunodeficiency 87 and autoimmunity, immunodeficiency 88, immunodeficiency 89 and autoimmunity, immunodeficiency 91 and hyperinflammation, immunodeficiency 92, immunodeficiency 93 and hypertrophic cardiomyopathy, immunodeficiency 95, immunodeficiency 96, immunodeficiency 97 with autoinflammation, immunodeficiency 99 with hypogammaglobulinemia and autoimmune cytopenias, immunodeficiency 101 (varicella zoster virus-specific), immunodeficiency 75, immunodeficiency 76, immunodeficiency 106, susceptibility to viral infections, immunodeficiency 78 with autoimmunity and developmental delay, immunodeficiency 77, immunodeficiency 107, susceptibility to invasive staphylococcus aureus infection, immunodeficiency 15a, immunodeficiency 60, immunodeficiency 62, immunodeficiency 63 with lymphoproliferation and autoimmunity, immunodeficiency 64, immunodeficiency 65, susceptibility to viral infections, immunodeficiency 69, immunodeficiency 70, immunodeficiency 72 with autoinflammation, GATA2 deficiency with susceptibility to MDS/AML, Shwachman-Diamond syndrome 1, immunodeficiency 53, immunodeficiency 11b with atopic dermatitis, IKBKG-related immunodeficiency with or without ectodermal dysplasia, FNIP1-associated syndrome, FASLG-related immunodeficiency, TNFRSF9-related immunodeficiency, DNAJC21-related Shwachman Diamond syndrome, IRF4-related immune disorder, PTEN harmartoma tumor syndrome with immune disorder, primary immunodeficiency due to calcium channel deficiency, chronic mucocutaneous candidiasis and connective tissue disease due to JNK1 haploinsufficiency, immune deficiency due to impaired neutrophil phagocytosis and migration, hatipoglu immunodeficiency syndrome, immunodeficiency 112, immunodeficiency 113 with autoimmunity and autoinflammation, immunodeficiency 114, folate-responsive, immunodeficiency 115 with autoinflammation, immunodeficiency 117, immunodeficiency 118, immunodeficiency 119, immunodeficiency 121 with autoinflammation, immunodeficiency 122, immunodeficiency 123 with HPV-related verrucosis, immunodeficiency 125, immunodeficiency 126, susceptibility to, immunodeficiency 127, immunodeficiency 128, immunodeficiency 132b, immunodeficiency 133 with ectodermal dysplasia with or without peripheral neuropathy, immunodeficiency 134 (Epstein-Barr virus-specific)

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

18 retrieved; paginated sample, class counts are floors:

7 uncertain significance, 7 benign, 2 conflicting classifications of pathogenicity, 1 benign/likely benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
587621	NM_001128148.3(TFRC):c.1198+1G>T	TFRC	Pathogenic	criteria provided, single submitter
1584510	NM_001128148.3(TFRC):c.310A>G (p.Thr104Ala)	TFRC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
218163	NM_001128148.3(TFRC):c.58T>C (p.Tyr20His)	TFRC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1028096	NM_001128148.3(TFRC):c.1181A>G (p.Lys394Arg)	TFRC	Uncertain significance	criteria provided, single submitter
1028097	NM_001128148.3(TFRC):c.1678-3C>T	TFRC	Uncertain significance	criteria provided, multiple submitters, no conflicts
1028098	NM_001128148.3(TFRC):c.464G>C (p.Arg155Pro)	TFRC	Uncertain significance	criteria provided, multiple submitters, no conflicts
1031313	NM_001128148.3(TFRC):c.2186C>T (p.Thr729Met)	TFRC	Uncertain significance	criteria provided, multiple submitters, no conflicts
1033985	NM_001128148.3(TFRC):c.1136A>G (p.Asn379Ser)	TFRC	Uncertain significance	criteria provided, multiple submitters, no conflicts
1357636	NM_001128148.3(TFRC):c.734A>G (p.Asp245Gly)	TFRC	Uncertain significance	criteria provided, multiple submitters, no conflicts
1417927	NM_001128148.3(TFRC):c.1661C>G (p.Ser554Cys)	TFRC	Uncertain significance	criteria provided, single submitter
1164901	NM_001128148.3(TFRC):c.687+9A>G	TFRC	Benign	criteria provided, multiple submitters, no conflicts
1164902	NM_001128148.3(TFRC):c.424G>A (p.Gly142Ser)	TFRC	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1166955	NM_001128148.3(TFRC):c.1678-12G>A	TFRC	Benign	criteria provided, multiple submitters, no conflicts
1168227	NM_001128148.3(TFRC):c.1404+17C>A	TFRC	Benign	criteria provided, multiple submitters, no conflicts
1230584	NM_001128148.3(TFRC):c.1678-5T>C	TFRC	Benign	criteria provided, multiple submitters, no conflicts
1237075	NM_001128148.3(TFRC):c.1678-4G>A	TFRC	Benign	criteria provided, multiple submitters, no conflicts
1238317	NM_001128148.3(TFRC):c.1468+25G>T	TFRC	Benign	criteria provided, multiple submitters, no conflicts
1273355	NM_001128148.3(TFRC):c.1468+39A>G	TFRC	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
TFRC	Definitive	Autosomal recessive	TFRC-related combined immunodeficiency	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TFRC	Orphanet:476113	Combined immunodeficiency due to TFRC deficiency

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TFRC	HGNC:11763	ENSG00000072274	P02786	Transferrin receptor protein 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TFRC	Transferrin receptor protein 1	Cellular uptake of iron occurs via receptor-mediated endocytosis of ligand-occupied transferrin receptor into specialized endosomes.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TFRC	Protease	yes		PA_domain, TFR-like_dimer_dom, Peptidase_M28

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
endothelial cell	1
tibia	1
trabecular bone tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TFRC	295	ubiquitous	marker	endothelial cell, trabecular bone tissue, tibia

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TFRC	6,725

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TFRC	P02786	24

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 29. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Transferrin endocytosis and recycling	1	368.4×	0.014	TFRC
Iron uptake and transport	1	346.1×	0.014	TFRC
RHOH GTPase cycle	1	308.6×	0.014	TFRC
Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin	1	278.5×	0.014	TFRC
RND1 GTPase cycle	1	265.6×	0.014	TFRC
RND2 GTPase cycle	1	259.6×	0.014	TFRC
trans-Golgi Network Vesicle Budding	1	253.8×	0.014	TFRC
Developmental Cell Lineages	1	223.9×	0.014	TFRC
Golgi Associated Vesicle Biogenesis	1	200.3×	0.014	TFRC
RHOJ GTPase cycle	1	200.3×	0.014	TFRC
RHOQ GTPase cycle	1	181.3×	0.014	TFRC
RHOB GTPase cycle	1	154.3×	0.014	TFRC
RHOG GTPase cycle	1	148.3×	0.014	TFRC
RHOC GTPase cycle	1	146.4×	0.014	TFRC
RAC2 GTPase cycle	1	126.9×	0.015	TFRC
RAC3 GTPase cycle	1	119.0×	0.015	TFRC
Cargo recognition for clathrin-mediated endocytosis	1	104.8×	0.016	TFRC
Clathrin-mediated endocytosis	1	85.2×	0.019	TFRC
RHOA GTPase cycle	1	74.6×	0.020	TFRC
CDC42 GTPase cycle	1	72.3×	0.020	TFRC
RAC1 GTPase cycle	1	61.1×	0.022	TFRC
RHO GTPase cycle	1	60.1×	0.022	TFRC
Membrane Trafficking	1	37.1×	0.033	TFRC
Vesicle-mediated transport	1	34.8×	0.033	TFRC
Signaling by Rho GTPases	1	34.2×	0.033	TFRC
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	33.5×	0.033	TFRC
Transport of small molecules	1	25.1×	0.043	TFRC
Developmental Biology	1	14.5×	0.072	TFRC
Signal Transduction	1	10.2×	0.098	TFRC

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to manganese ion	1	2808.7×	0.004	TFRC
negative regulation of mitochondrial fusion	1	2106.5×	0.004	TFRC
transferrin transport	1	1532.0×	0.004	TFRC
response to copper ion	1	1532.0×	0.004	TFRC
positive regulation of isotype switching	1	1296.3×	0.004	TFRC
response to iron ion	1	936.2×	0.005	TFRC
iron ion transport	1	887.0×	0.005	TFRC
multicellular organismal-level iron ion homeostasis	1	581.1×	0.006	TFRC
regulation of postsynaptic membrane neurotransmitter receptor levels	1	495.6×	0.006	TFRC
acute-phase response	1	421.3×	0.006	TFRC
positive regulation of protein localization to nucleus	1	391.9×	0.006	TFRC
response to retinoic acid	1	383.0×	0.006	TFRC
osteoclast differentiation	1	343.9×	0.006	TFRC
positive regulation of B cell proliferation	1	343.9×	0.006	TFRC
positive regulation of protein-containing complex assembly	1	337.0×	0.006	TFRC
receptor internalization	1	324.1×	0.006	TFRC
response to nutrient	1	295.6×	0.006	TFRC
positive regulation of T cell proliferation	1	259.3×	0.006	TFRC
intracellular iron ion homeostasis	1	244.2×	0.006	TFRC
cellular response to xenobiotic stimulus	1	240.7×	0.006	TFRC
receptor-mediated endocytosis	1	221.7×	0.006	TFRC
transport across blood-brain barrier	1	179.3×	0.007	TFRC
cellular response to leukemia inhibitory factor	1	159.0×	0.008	TFRC
response to hypoxia	1	95.8×	0.013	TFRC
positive regulation of canonical NF-kappaB signal transduction	1	72.6×	0.016	TFRC
cell surface receptor signaling pathway	1	64.1×	0.017	TFRC
positive regulation of gene expression	1	38.7×	0.027	TFRC
intracellular signal transduction	1	38.1×	0.027	TFRC
negative regulation of apoptotic process	1	34.8×	0.029	TFRC

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TFRC	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
TFRC	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	TFRC
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
TFRC	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.