FXN

frataxin, the group of Mitochondrial iron-sulfur assembly components

Basic information

Region (hg38): 9:69035750-69079076

Previous symbols: [ "FRDA" ]

Links

ENSG00000165060 ∙ NCBI:2395 ∙ OMIM:606829 ∙ HGNC:3951 ∙ Uniprot:Q16595 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Friedreich ataxia (Supportive), mode of inheritance: AR
• Friedreich ataxia (Definitive), mode of inheritance: AR
• Friedreich ataxia 1 (Strong), mode of inheritance: AR
• Friedreich ataxia (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Friedreich ataxia 1	AR	Cardiovascular	Though frequently clinically recognizable, the majority of individuals have cardiomyopathy, and medications (eg, antiarrhythmics, medications for cardiac-failure, anticoagulants, and pacemaker insertion) may be beneficial; Heart transplantation has been described	Cardiovascular; Endocrine; Musculoskeletal; Neurologic; Ophthalmologic	13872187; 5673214; 5533984; 4206197; 7272714; 6231891; 8057123; 7695235; 8596916; 8623752; 8815938; 8751856; 9150176; 9142000; 9245990; 9259271; 9539351; 10399865; 10543403; 10533031; 10500204; 11425956; 11843702; 11857753; 15539131; 19347027; 20301458; 21700145; 21570254; 22409940; 22522441; 22691228; 22752483; 22752493; 22764179; 23196337; 23242090

ClinVar

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

• not provided (57 variants)
• Inborn genetic diseases (28 variants)
• not specified (9 variants)
• Friedreich ataxia 1 (4 variants)
• Friedreich ataxia (3 variants)
• Hypertrophic cardiomyopathy (1 variants)
• Cardiovascular phenotype (1 variants)
• Charcot-Marie-Tooth-like disease (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the FXN 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	9	2	13
missense	2		29	2	2	35
nonsense	1	1				2
start loss	1		1		1	3
frameshift	2	1				3
inframe indel						0
splice donor/acceptor (+/-2bp)		2				2
splice region		2	1			3
non coding	1		3		14	18
Total	7	4	35	11	19

Highest pathogenic variant AF is 0.0000591

Variants in FXN

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

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

Position	Type	Phenotype	Significance	ClinVar
9-69035774-C-G			Uncertain significance (Feb 28, 2020)
9-69035776-G-A		not specified	Benign (Nov 03, 2023)
9-69035785-G-T		Friedreich ataxia • Friedreich ataxia 1	Pathogenic (Apr 12, 2022)
9-69035789-ACT-A		Inborn genetic diseases • Friedreich ataxia 1	Pathogenic/Likely pathogenic (Aug 23, 2023)
9-69035796-G-C		Inborn genetic diseases	Uncertain significance (Jan 11, 2023)
9-69035816-C-G			Uncertain significance (Sep 16, 2017)
9-69035823-C-A			Benign (Jul 05, 2019)
9-69035823-C-T		Inborn genetic diseases	Uncertain significance (Feb 03, 2022)
9-69035828-C-T		Inborn genetic diseases	Uncertain significance (Jul 08, 2022)
9-69035832-G-T		Inborn genetic diseases	Uncertain significance (Dec 26, 2023)
9-69035836-A-G		not specified • Friedreich ataxia 1 • Inborn genetic diseases	Benign (Nov 29, 2023)
9-69035837-G-A		Inborn genetic diseases	Uncertain significance (Mar 02, 2018)
9-69035850-C-T		not specified	Benign (Sep 15, 2020)
9-69035852-C-T		Inborn genetic diseases	Uncertain significance (Jan 23, 2023)
9-69035858-C-T		Inborn genetic diseases	Uncertain significance (Apr 26, 2023)
9-69035863-C-T			Uncertain significance (Aug 24, 2020)
9-69035879-T-C		Inborn genetic diseases	Likely benign (May 31, 2016)
9-69035879-T-G			Uncertain significance (Sep 02, 2021)
9-69035886-C-T		Inborn genetic diseases	Uncertain significance (Jun 22, 2023)
9-69035887-A-C			Likely benign (Oct 01, 2023)
9-69035894-G-A		Inborn genetic diseases	Likely benign (Jun 02, 2023)
9-69035900-C-T		not specified • Hypertrophic cardiomyopathy • Inborn genetic diseases	Conflicting classifications of pathogenicity (Oct 21, 2022)
9-69035905-C-T			Conflicting classifications of pathogenicity (May 30, 2019)
9-69035907-T-G			Uncertain significance (Apr 12, 2023)
9-69035910-G-A		not specified • Inborn genetic diseases	Uncertain significance (Nov 14, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
FXN	protein_coding	protein_coding	ENST00000377270	5	64920

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.345	0.643	125743	0	5	125748	0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.284	94	102	0.921	0.00000567	1321
Missense in Polyphen		28	35.664	0.7851		446
Synonymous	-0.336	48	45.1	1.06	0.00000282	432
Loss of Function	2.11	2	8.70	0.230	3.70e-7	114

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000578	0.0000578
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.0000176	0.0000176
Middle Eastern	0.0000544	0.0000544
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Promotes the biosynthesis of heme and assembly and repair of iron-sulfur clusters by delivering Fe(2+) to proteins involved in these pathways. May play a role in the protection against iron-catalyzed oxidative stress through its ability to catalyze the oxidation of Fe(2+) to Fe(3+); the oligomeric form but not the monomeric form has in vitro ferroxidase activity. May be able to store large amounts of iron in the form of a ferrihydrite mineral by oligomerization; however, the physiological relevance is unsure as reports are conflicting and the function has only been shown using heterologous overexpression systems. Modulates the RNA-binding activity of ACO1. {ECO:0000269|PubMed:12785837, ECO:0000269|PubMed:15247478, ECO:0000269|PubMed:15641778, ECO:0000269|PubMed:16239244, ECO:0000269|PubMed:16608849, ECO:0000269|PubMed:20053667}.
• Disease: DISEASE: Friedreich ataxia (FRDA) [MIM:229300]: Autosomal recessive, progressive degenerative disease characterized by neurodegeneration and cardiomyopathy it is the most common inherited ataxia. The disorder is usually manifest before adolescence and is generally characterized by incoordination of limb movements, dysarthria, nystagmus, diminished or absent tendon reflexes, Babinski sign, impairment of position and vibratory senses, scoliosis, pes cavus, and hammer toe. In most patients, FRDA is due to GAA triplet repeat expansions in the first intron of the frataxin gene. But in some cases the disease is due to mutations in the coding region. {ECO:0000269|PubMed:10732799, ECO:0000269|PubMed:10874325, ECO:0000269|PubMed:19629184, ECO:0000269|PubMed:9150176, ECO:0000269|PubMed:9779809, ECO:0000269|PubMed:9989622, ECO:0000269|Ref.36, ECO:0000269|Ref.7, ECO:0000269|Ref.8}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Porphyrin and chlorophyll metabolism - Homo sapiens (human);Metabolism of proteins;HIF-2-alpha transcription factor network;Mitochondrial iron-sulfur cluster biogenesis;Metabolism;Mitochondrial protein import (Consensus)

Recessive Scores

• pRec: 0.390

Intolerance Scores

• loftool: 0.0158
• rvis_EVS: 0.41
• rvis_percentile_EVS: 76.67

Haploinsufficiency Scores

• pHI: 0.331
• hipred: Y
• hipred_score: 0.552
• ghis: 0.413

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.762

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Fxn
• Phenotype: growth/size/body region phenotype; muscle phenotype; homeostasis/metabolism phenotype; immune system phenotype; cellular phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); embryo phenotype; 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); 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); 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)

Gene ontology

• Biological process: oxidative phosphorylation;heme biosynthetic process;ion transport;cellular iron ion homeostasis;mitochondrion organization;adult walking behavior;positive regulation of cell population proliferation;aerobic respiration;embryo development ending in birth or egg hatching;response to iron ion;regulation of ferrochelatase activity;iron-sulfur cluster assembly;protein autoprocessing;iron incorporation into metallo-sulfur cluster;proprioception;positive regulation of cell growth;negative regulation of multicellular organism growth;negative regulation of apoptotic process;positive regulation of catalytic activity;small molecule metabolic process;negative regulation of organ growth;positive regulation of lyase activity;cellular response to hydrogen peroxide;negative regulation of release of cytochrome c from mitochondria;positive regulation of succinate dehydrogenase activity;positive regulation of aconitate hydratase activity
• Cellular component: mitochondrion;mitochondrial matrix;cytosol;L-cysteine desulfurase complex
• Molecular function: ferroxidase activity;protein binding;ferrous iron binding;ferric iron binding;iron chaperone activity;2 iron, 2 sulfur cluster binding