TF

protein-coding

transferrin, the group of Transferrins

Gene summary

This gene encodes a glycoprotein with an approximate molecular weight of 76.5 kDa. It is thought to have been created as a result of an ancient gene duplication event that led to generation of homologous C and N-terminal domains each of which binds one ion of ferric iron. The function of this protein is to transport iron from the intestine, reticuloendothelial system, and liver parenchymal cells to all proliferating cells in the body. This protein may also have a physiologic role as granulocyte/pollen-binding protein (GPBP) involved in the removal of certain organic matter and allergens from serum. [provided by RefSeq, Sep 2009]

MANE transcript

NM_001063.4

Inheritance

ClinVar variants

P:18U:102B:197

Top phenotype

Atransferrinemia

gnomAD constraint

pLI —, LoF o/e 0.51

Max pathogenic AF

—

Genomic locus

chr3:133,746,040-133,796,641

External References & Databases

Ensembl (ENSG00000091513)

Transcript & Mutation Effects

hg38 • Region Span ~50.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

atransferrinemiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008846

Submitter: PanelApp Australia

atransferrinemiaMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0008846

Submitter: ClinGen

*TF* was first reported in relation to autosomal recessive atransferrinemia in 2000 (Beutler E et al., PMID:11110675). Although reports of a transferrin defect causing congenital atransferrinemia date back to 1961. Cases first identified in the 1900s that have since been genotyped are scored in this curation. Atransferrinemia is a rare hematologic disease characterized by microcytic, hypochromic anemia and iron overload, and that can be fatal if left untreated. Some patients present with pallor, fatigue, and growth retardation. Ten variants (eight missense, one synonymous, one frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in 9 probands in 7 publications (PMIDs:11110675, 32028041, 12111369, 15466165, 23888904, 18097132, 19696475). This gene-disease relationship is supported by biochemical function, an expression study, and a mouse model (PMIDs:10945247, 25970244, 10910930). The biochemical function of *TF* in iron binding and transport is well established. This role is consistent with the phenotype of the patients scored in this curation. The kinetic studies and X-ray crystallography supporting this function are reviewed by Hirose (PMID:10945247). RNA sequencing of total RNA from 20 human tissues shows specific expression in the liver and fetal liver, relevant tissues to this disease (PMID:25970244). A known hypotransferrinemic mouse line, exhibiting transferrin deficiency, marked anemia, hyperabsorption of iron, and elevated hepatic iron, was investigated and found to have a splice defect in the mouse transferrin gene (PMID:10910930). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen General Inborn Errors of Metabolism GCEP on the meeting date September 26, 2025.

atransferrinemiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008846

Submitter: Orphanet

atransferrinemiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008846

Submitter: Genomics England PanelApp

atransferrinemiaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0008846

Submitter: Ambry Genetics

atransferrinemiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008846

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

AtransferrinemiaAR

Manifestation: Hematologic

Intervention: Hematologic

Rationale: The condition, which involves microcytic anemia and iron overload, can have insidious, nonspecific, and severe manifestations that may include congestive heart failure, and treatment with plasma infusion has been described as effective

Refs: 13906010; 4625559; 8317485; 11110675; 15466165; 18097132; 19579082

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TF variants in ClinVar

10 Conditions Cataloged

not providedTotal: 364

not specifiedTotal: 80

AtransferrinemiaTotal: 66

TF-related disorderTotal: 9

Transferrin variant D1Total: 1

Prostate cancerTotal: 1

Transferrin variant B2Total: 1

Transferrin variant BvTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001063.4. 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			2 clinvar	178 clinvar	6 clinvar	186
missense	5 clinvar	2 clinvar	95 clinvar	11 clinvar	2 clinvar	115
nonsense		4 clinvar	1 clinvar			5
start loss						0
frameshift	1 clinvar	3 clinvar	1 clinvar			5
splice donor/acceptor (+/-2bp)		3 clinvar	3 clinvar			6
Total	6	12	102	189	8	317

Highest pathogenic variant AF is 0.000008054543

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 92 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001063.4	RefSeq	NP_001054.2	17	MANE Select
ENST00000402696.9	Ensembl	ENSP00000385834.3	17	MANE Select
NM_001354703.2	RefSeq	NP_001341632.2	16	Standard
NM_001354704.2	RefSeq	NP_001341633.2	14	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
tfa	Danio rerio	Structure: nucleate erythrocyte Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

tfa

Danio rerio

Structure: nucleate erythrocyte

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

HIF-1 signaling pathway - Homo sapiens (human)
Mineral absorption - Homo sapiens (human)
Ferroptosis - Homo sapiens (human)
Iron metabolism in placenta
Differentiation Pathway

Biological Process

retina homeostasis
platelet degranulation
cellular iron ion homeostasis
regulation of protein stability
transferrin transport

Molecular Function

protein binding
ferrous iron binding
ferric iron binding
ferric iron transmembrane transporter activity
iron chaperone activity

Cellular Component

extracellular region
extracellular space
early endosome
late endosome
endoplasmic reticulum lumen

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000402696
Coding exons: 17
Length: 33051
Individuals with no LoFs: 125714
Homozygous LoFs: 0
Heterozygous LoFs: 34
Defined: 125748
p: 0.000135

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.46	304	385	0.790	0.0000220	4577
Missense (PolyPhen)		118	156.29	0.75502		1918
Synonymous	-1.60	179	154	1.16	0.00000971	1312
Loss of Function	2.72	18	35.4	0.508	0.00000170	459

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00017	0.00017	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00014	0.00014	rare
South Asian	0.00013	0.00013	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transferrins are iron binding transport proteins which can bind two Fe(3+) ions in association with the binding of an anion, usually bicarbonate. It is responsible for the transport of iron from sites of absorption and heme degradation to those of storage and utilization. Serum transferrin may also have a further role in stimulating cell proliferation.;
Disease: DISEASE: Atransferrinemia (ATRAF) [MIM:209300]: A rare autosomal recessive disorder characterized by abnormal synthesis of transferrin leading to iron overload and microcytic hypochromic anemia. {ECO:0000269|PubMed:11110675, ECO:0000269|PubMed:15466165}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.948

Intolerance Scores

LoFtool: 0.248
RVIS EVS: -0.91
RVIS percentile EVS: 10.12

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.919

Gene Damage Prediction

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