TFR2

transferrin receptor 2, the group of M28 metallopeptidases

Basic information

Region (hg38): 7:100620415-100642779

Links

ENSG00000106327 ∙ NCBI:7036 ∙ OMIM:604720 ∙ HGNC:11762 ∙ Uniprot:Q9UP52 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hemochromatosis type 3 (Strong), mode of inheritance: AR
• hemochromatosis type 3 (Strong), mode of inheritance: AR
• hemochromatosis type 3 (Supportive), mode of inheritance: AR
• hemochromatosis type 3 (Definitive), mode of inheritance: AR
• hemochromatosis type 3 (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hemochromatosis, type 3	AR	Biochemical; Gastrointestinal; Hematologic	Preventive measures and treatment of iron overload (by phlebotomy) can be beneficial	Biochemical; Cardiovascular; Endocrine; Gastrointestinal; Hematologic	10216143; 10802645; 12150153; 12130528; 19549277; 20542038; 21770687
Variants may also modify hemochromatosis due to mutations in other genes (eg, HFE)

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TFR2 gene.

• Hereditary hemochromatosis (648 variants)
• Hemochromatosis type 3 (196 variants)
• Inborn genetic diseases (34 variants)
• not provided (26 variants)
• not specified (7 variants)
• Hemochromatosis type 1 (5 variants)
• TFR2-related condition (2 variants)
• Hereditary hemochromatosis type 4 (1 variants)
• Hereditary hemochromatosis type 5 (1 variants)
• Hemochromatosis, type 1, modifier of (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TFR2 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			3	313	5	321
missense	1	3	101	9	1	115
nonsense	11	15				26
start loss			1			1
frameshift	25	20				45
inframe indel		2	1			3
splice donor/acceptor (+/-2bp)	2	24				26
splice region		1	10	58	3	72
non coding			11	75	13	99
Total	39	64	117	397	19

Highest pathogenic variant AF is 0.0000526

Variants in TFR2

This is a list of pathogenic ClinVar variants found in the TFR2 region.

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

Position	Type	Phenotype	Significance	ClinVar
7-100620422-A-G		Hemochromatosis type 3	Uncertain significance (Jan 12, 2018)
7-100620577-T-G		Hemochromatosis type 3	Uncertain significance (Jan 13, 2018)
7-100620637-G-A		Hemochromatosis type 3	Uncertain significance (Jan 13, 2018)
7-100620649-G-A		Hemochromatosis type 3	Uncertain significance (Jan 13, 2018)
7-100620715-C-T		Hemochromatosis type 3	Uncertain significance (Jan 13, 2018)
7-100620716-G-A		Hemochromatosis type 3	Uncertain significance (Jan 13, 2018)
7-100620741-G-A		Hemochromatosis type 3	Likely benign (Jan 13, 2018)
7-100620802-C-T		Hemochromatosis type 3	Uncertain significance (Jan 13, 2018)
7-100620856-C-T		Hemochromatosis type 3	Uncertain significance (Jan 13, 2018)
7-100620863-G-A		Hereditary hemochromatosis • Hemochromatosis type 3	Likely benign (Jan 07, 2024)
7-100620867-T-C		Inborn genetic diseases	Uncertain significance (Mar 17, 2023)
7-100620869-A-G		Hereditary hemochromatosis	Likely benign (Dec 18, 2023)
7-100620874-T-C		Hereditary hemochromatosis	Likely benign (Jan 25, 2024)
7-100620881-G-A		Hereditary hemochromatosis	Likely benign (Jul 31, 2022)
7-100620884-A-G		Hereditary hemochromatosis	Likely benign (Apr 07, 2023)
7-100620887-C-T		Hereditary hemochromatosis • TFR2-related disorder	Likely benign (Dec 19, 2023)
7-100620889-C-T		Hemochromatosis type 3 • Hereditary hemochromatosis	Likely pathogenic (Jan 11, 2024)
7-100620890-G-A		Hereditary hemochromatosis	Likely benign (Jan 05, 2024)
7-100620896-C-T		Hereditary hemochromatosis • Hemochromatosis type 3	Conflicting classifications of pathogenicity (Jan 16, 2024)
7-100620908-C-T		Hereditary hemochromatosis	Likely benign (Jan 13, 2024)
7-100620914-C-T		Hereditary hemochromatosis	Likely benign (Aug 18, 2023)
7-100620917-C-A		Hereditary hemochromatosis	Likely benign (Nov 01, 2023)
7-100620917-C-T		Hereditary hemochromatosis • Hemochromatosis type 3	Likely benign (Jan 28, 2024)
7-100620919-T-C		Inborn genetic diseases	Uncertain significance (Jun 24, 2022)
7-100620920-C-T		Hereditary hemochromatosis • Hemochromatosis type 3	Pathogenic/Likely pathogenic (Jul 17, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TFR2	protein_coding	protein_coding	ENST00000462107	18	22364

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.29e-9	0.997	125689	0	59	125748	0.000235

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.15	401	471	0.852	0.0000284	5109
Missense in Polyphen		127	170.18	0.74628		1801
Synonymous	1.18	184	206	0.895	0.0000132	1663
Loss of Function	2.72	21	39.4	0.533	0.00000191	416

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00118	0.00114
Ashkenazi Jewish	0.00	0.00
East Asian	0.000116	0.000109
Finnish	0.00	0.00
European (Non-Finnish)	0.000131	0.000123
Middle Eastern	0.000116	0.000109
South Asian	0.000196	0.000196
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Mediates cellular uptake of transferrin-bound iron in a non-iron dependent manner. May be involved in iron metabolism, hepatocyte function and erythrocyte differentiation.
• Pathway: Iron metabolism in placenta;Transferrin endocytosis and recycling;Transport of small molecules;Iron uptake and transport (Consensus)

Intolerance Scores

• loftool: 0.713
• rvis_EVS: -0.53
• rvis_percentile_EVS: 20.91

Haploinsufficiency Scores

• pHI: 0.397
• hipred: N
• hipred_score: 0.432
• ghis: 0.637

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• gene_indispensability_pred: E
• gene_indispensability_score: 0.887

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Tfr2
• Phenotype: hematopoietic system phenotype; liver/biliary system phenotype; immune system phenotype; growth/size/body region phenotype; homeostasis/metabolism phenotype

Zebrafish Information Network

• Gene name: tfr2
• Affected structure: muscle
• Phenotype tag: abnormal
• Phenotype quality: increased amount

Gene ontology

• Biological process: iron ion transport;cellular iron ion homeostasis;receptor-mediated endocytosis;acute-phase response;response to iron ion;transferrin transport;positive regulation of endocytosis;positive regulation of transcription by RNA polymerase II;iron ion homeostasis;cellular response to iron ion;positive regulation of peptide hormone secretion;positive regulation of protein maturation
• Cellular component: plasma membrane;integral component of plasma membrane;external side of plasma membrane;cytoplasmic vesicle;HFE-transferrin receptor complex
• Molecular function: transferrin receptor activity;protein binding;transferrin transmembrane transporter activity;co-receptor binding