ACTN3 (actinin alpha 3)

Gene

• Entrez ID: 89
• Gene name: Actinin alpha 3
• Gene symbol: ACTN3
• Synonyms (NCBI Gene): ACTN3D
• Chromosome: 11
• Chromosome location: 11q13.2
• Summary: This gene encodes a member of the alpha-actin binding protein gene family. The encoded protein is primarily expressed in skeletal muscle and functions as a structural component of sarcomeric Z line. This protein is involved in crosslinking actin containin

SNPs

SNP ID	Visualize variation	Clinical significance	Consequence
rs1815739	C>A,T	Benign, pathogenic, affects	Stop gained, synonymous variant, coding sequence variant

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0003779	Function	Actin binding	IEA
GO:0005178	Function	Integrin binding	IEA
GO:0005178	Function	Integrin binding	TAS	8104223
GO:0005509	Function	Calcium ion binding	IEA
GO:0005515	Function	Protein binding	IPI	11171996, 11309420, 32296183
GO:0005737	Component	Cytoplasm	IEA
GO:0005829	Component	Cytosol	TAS
GO:0005884	Component	Actin filament	TAS	1339456
GO:0005886	Component	Plasma membrane	IBA
GO:0005903	Component	Brush border	IEA
GO:0005925	Component	Focal adhesion	IMP	16807302
GO:0008307	Function	Structural constituent of muscle	TAS	1339456
GO:0014728	Process	Regulation of the force of skeletal muscle contraction	IEA
GO:0014728	Process	Regulation of the force of skeletal muscle contraction	ISS
GO:0014732	Process	Skeletal muscle atrophy	IEA
GO:0014732	Process	Skeletal muscle atrophy	ISS
GO:0014883	Process	Transition between fast and slow fiber	IEA
GO:0014883	Process	Transition between fast and slow fiber	ISS
GO:0014894	Process	Response to denervation involved in regulation of muscle adaptation	IEA
GO:0014894	Process	Response to denervation involved in regulation of muscle adaptation	ISS
GO:0015629	Component	Actin cytoskeleton	IEA
GO:0030017	Component	Sarcomere	IEA
GO:0030018	Component	Z disc	IBA
GO:0030018	Component	Z disc	IEA
GO:0030036	Process	Actin cytoskeleton organization	IBA
GO:0030054	Component	Cell junction	IBA
GO:0030054	Component	Cell junction	IEA
GO:0030864	Component	Cortical actin cytoskeleton	IBA
GO:0031143	Component	Pseudopodium	IEA
GO:0031143	Component	Pseudopodium	TAS	1629252
GO:0031448	Process	Positive regulation of fast-twitch skeletal muscle fiber contraction	IEA
GO:0042802	Function	Identical protein binding	IEA
GO:0042802	Function	Identical protein binding	IPI	32296183
GO:0042981	Process	Regulation of apoptotic process	NAS	16807302
GO:0042995	Component	Cell projection	IBA
GO:0044325	Function	Transmembrane transporter binding	IEA
GO:0044325	Function	Transmembrane transporter binding	IPI	19943616
GO:0045820	Process	Negative regulation of glycolytic process	IEA
GO:0045820	Process	Negative regulation of glycolytic process	ISS
GO:0046872	Function	Metal ion binding	IEA
GO:0048041	Process	Focal adhesion assembly	IMP	16807302
GO:0048633	Process	Positive regulation of skeletal muscle tissue growth	IEA
GO:0048633	Process	Positive regulation of skeletal muscle tissue growth	ISS
GO:0048743	Process	Positive regulation of skeletal muscle fiber development	IEA
GO:0051015	Function	Actin filament binding	IBA
GO:0051015	Function	Actin filament binding	IEA
GO:0055001	Process	Muscle cell development	IBA
GO:0060349	Process	Bone morphogenesis	IEA
GO:0070062	Component	Extracellular exosome	HDA	23533145
GO:0070885	Process	Negative regulation of calcineurin-NFAT signaling cascade	IEA
GO:0070885	Process	Negative regulation of calcineurin-NFAT signaling cascade	ISS
GO:0090257	Process	Regulation of muscle system process	IEA
GO:0090324	Process	Negative regulation of oxidative phosphorylation	IEA
GO:0090324	Process	Negative regulation of oxidative phosphorylation	ISS
GO:0120163	Process	Negative regulation of cold-induced thermogenesis	IEA
GO:0120163	Process	Negative regulation of cold-induced thermogenesis	ISS	25590636
GO:1900159	Process	Positive regulation of bone mineralization involved in bone maturation	IEA
GO:1901078	Process	Negative regulation of relaxation of muscle	IEA
GO:1903715	Process	Regulation of aerobic respiration	IEA
GO:1903715	Process	Regulation of aerobic respiration	ISS
GO:1904025	Process	Positive regulation of glucose catabolic process to lactate via pyruvate	IEA
GO:1904025	Process	Positive regulation of glucose catabolic process to lactate via pyruvate	ISS

Other IDs

• MIM: 102574
• HGNC: 165
• e!Ensembl: ENSG00000248746

Protein

• UniProt ID: Q08043
• Protein name: Alpha-actinin-3 (Alpha-actinin skeletal muscle isoform 3) (F-actin cross-linking protein)
• Protein function: F-actin cross-linking protein which is thought to anchor actin to a variety of intracellular structures. This is a bundling protein.
• PDB: 1TJT, 1WKU, 3LUE
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF00307	CH	45 → 150	Calponin homology (CH) domain	Domain
  PF00307	CH	158 → 265	Calponin homology (CH) domain	Domain
  PF00435	Spectrin	288 → 398	Spectrin repeat	Domain
  PF00435	Spectrin	408 → 513	Spectrin repeat	Domain
  PF00435	Spectrin	523 → 634	Spectrin repeat	Domain
  PF00435	Spectrin	644 → 747	Spectrin repeat	Domain
  PF08726	EFhand_Ca_insen	831 → 897	Ca2+ insensitive EF hand	Domain

• Tissue specificity: TISSUE SPECIFICITY: Expression restricted to fast (type 2) skeletal muscle fibers (at protein level). {ECO:0000269|PubMed:10192379, ECO:0000269|PubMed:11440986}.
• Sequence:

  MMMVMQPEGLGAGEGRFAGGGGGGEYMEQEEDWDRDLLLDPAWEKQQRKTFTAWCNSHLR
  KAGTQIENIEEDFRNGLKLMLLLEVISGERLPRPDKGKMRFHKIANVNKALDFIASKGVK
  LVSIGAEEIVDGNLKMTLGMIWTIILRFAIQDISVEETSAKEGLLLWCQRKTAPYRNVNV
  QNFHTSWKDGLALCALIHRHRPDLIDYAKLRKDDPIGNLNTAFEVAEKYLDIPKMLDAED
  IVNTPKPDEKAIMTYVSCFYHAFAGAEQAETAANRICKVLAVNQENEKLMEEYEKLASEL
  LEWIRRTVPWLENRVGEPSMSAMQRKLEDFRDYRRLHKPPRIQEKCQLEINFNTLQTKLR
  LSHRPAFMPSEGKLVSDIANAWRGLEQVEKGYEDWLLSEIRRLQRLQHLAEKFRQKASLH
  EAWTRGKEEMLSQRDYDSALLQEVRALLRRHEAFESDLAAHQDRVEHIAALAQELNELDY
  HEAASVNSRCQAICDQWDNLGTLTQKRRDALERMEKLLETIDRLQLEFARRAAPFNNWLD
  GAVEDLQDVWLVHSVEETQSLLTAHDQFKATLPEADRERGAIMGIQGEIQKICQTYGLRP
  CSTNPYITLSPQDINTKWDMVRKLVPSCDQTLQEELARQQVNERLRRQFAAQANAIGPWI
  QAKVEEVGRLAAGLAGSLEEQMAGLRQQEQNIINYKTNIDRLEGDHQLLQESLVFDNKHT
  VYSMEHIRVGWEQLLTSIARTINEVENQVLTRDAKGLSQEQLNEFRASFNHFDRKQNGMM
  EPDDFRACLISMGYDLGEVEFARIMTMVDPNAAGVVTFQAFIDFMTRETAETDTTEQVVA
  SFKILAGDKNYITPEELRRELPAKQAEYCIRRMVPYKGSGAPAGALDYVAFSSALYGESD
  L

• Sequence length: 901

Pathways

KEGG:

Cytoskeleton in muscle cells
Arrhythmogenic right ventricular cardiomyopathy

Reactome:

Striated Muscle Contraction

Associated diseases

Evidence Score:

• ★☆☆☆☆  Gene-disease association found in Text Mining only
• ★★☆☆☆  Found in Text Mining and Unknown/Other Associations
• ★★★☆☆  Reported in Unknown/Other Associations across ≥2 Sources
• ★★★★☆  ClinVar: Pathogenic/Likely Pathogenic (<5 Variants)
• ★★★★★  ClinVar: Pathogenic/Likely Pathogenic (≥5 Variants)

Unknown / Other Associations
Phenotype Name	Clinical Significance	Source	Evidence Score
ACTN3-related disorder	Uncertain significance; Likely benign; Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
ASTHMA	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
BIPOLAR DISORDER	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
FRONTOTEMPORAL DEMENTIA	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
INSOMNIA	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
SLEEP APNEA	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
ULCERATIVE COLITIS	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Uterine carcinosarcoma	Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations

Associations from Text Mining
Disease Name	Disease (Merged)	Source	PMID	Relationship Type	Evidence Score
ACTN3 DEFICIENCY	ACTN3 DEFICIENCY	BEFREE	11440986, 18178581, 21112313, 22639897, 25590636, 25761735, 26802899, 28254467, 28817413, 30281865, 31481717		★☆☆☆☆ Found in Text Mining only
ACTN3 DEFICIENCY	ACTN3 DEFICIENCY	CLINVAR_DG			★☆☆☆☆ Found in Text Mining only
Adult type dermatomyositis	Dermatomyositis	BEFREE	22639897		★☆☆☆☆ Found in Text Mining only
Amyotrophic Lateral Sclerosis	Amyotrophic Lateral Sclerosis	BEFREE	21375368		★☆☆☆☆ Found in Text Mining only
Amyotrophic Lateral Sclerosis	Amyotrophic lateral sclerosis	Pubtator	23469062	Associate	★☆☆☆☆ Found in Text Mining only
Bruxism	Bruxism	Pubtator	32552448, 34773324	Associate	★☆☆☆☆ Found in Text Mining only
CAMPOMELIC DYSPLASIA	Campomelic Dysplasia	BEFREE	9309713		★☆☆☆☆ Found in Text Mining only
Carcinoma, Ovarian Epithelial	Ovarian Epithelial carcinoma	BEFREE	24615723		★☆☆☆☆ Found in Text Mining only
Chronic heart failure	Heart Failure	BEFREE	25059829		★☆☆☆☆ Found in Text Mining only
Cone-Rod Dystrophy 2	Cone-rod dystrophy	BEFREE	23145141		★☆☆☆☆ Found in Text Mining only
Congestive heart failure	Congestive Heart Failure	BEFREE	25059829		★☆☆☆☆ Found in Text Mining only
CRANIOMETAPHYSEAL DYSPLASIA, AUTOSOMAL DOMINANT	Craniometaphyseal Dysplasia	BEFREE	9309713		★☆☆☆☆ Found in Text Mining only
Dermatomyositis	Dermatomyositis	BEFREE	22639897		★☆☆☆☆ Found in Text Mining only
Distal Myopathies	Distal myopathy	Pubtator	32726330	Associate	★☆☆☆☆ Found in Text Mining only
Generalized glycogen storage disease of infants	Glycogen Storage Disease	BEFREE	25103075		★☆☆☆☆ Found in Text Mining only
Glycogen storage disease type II	Glycogen Storage Disease	BEFREE	25103075		★☆☆☆☆ Found in Text Mining only
Glycogen Storage Disease Type II	Glycogen storage disease	Pubtator	25103075, 34734785	Associate	★☆☆☆☆ Found in Text Mining only
Glycogen Storage Disease Type V	Glycogen Storage Disease	BEFREE	17560787, 19232494, 30281865		★☆☆☆☆ Found in Text Mining only
Glycogen Storage Disease Type V	Glycogen Storage Disease	LHGDN	17560787		★☆☆☆☆ Found in Text Mining only
Glycogen Storage Disease Type V	Glycogen storage disease	Pubtator	35563042	Inhibit	★☆☆☆☆ Found in Text Mining only
Heart Failure	Heart failure	Pubtator	25059829	Associate	★☆☆☆☆ Found in Text Mining only
Hypertension	Hypertension	Pubtator	25059829	Associate	★☆☆☆☆ Found in Text Mining only
Idiopathic Inflammatory Myopathies	Inflammatory Myopathy	BEFREE	22639897		★☆☆☆☆ Found in Text Mining only
Insulin Resistance	Diabetes mellitus, type 2	Pubtator	21299892	Associate	★☆☆☆☆ Found in Text Mining only
Malignant neoplasm of ovary	Ovarian cancer	BEFREE	24615723		★☆☆☆☆ Found in Text Mining only
Malocclusion	Malocclusion	Pubtator	25439211, 29103441	Associate	★☆☆☆☆ Found in Text Mining only
Metabolic Syndrome	Metabolic syndrome	Pubtator	26107372	Associate	★☆☆☆☆ Found in Text Mining only
Metabolic Syndrome X	Metabolic Syndrome	BEFREE	26483160		★☆☆☆☆ Found in Text Mining only
Muscular Dystrophy	Muscular dystrophy	BEFREE	9309713		★☆☆☆☆ Found in Text Mining only
Muscular Dystrophy Duchenne	Duchenne muscular dystrophy	Pubtator	32343055, 35897138	Associate	★☆☆☆☆ Found in Text Mining only
Muscular Dystrophy, Duchenne	Duchenne Muscular Dystrophy	BEFREE	28139640		★☆☆☆☆ Found in Text Mining only
Myopathy	Myopathy	BEFREE	28817413, 30281865		★☆☆☆☆ Found in Text Mining only
Myositis	Myositis	BEFREE	22639897		★☆☆☆☆ Found in Text Mining only
Neuromuscular Diseases	Neuromuscular disease	Pubtator	39808562	Associate	★☆☆☆☆ Found in Text Mining only
Obesity	Obesity	BEFREE	28293018		★☆☆☆☆ Found in Text Mining only
Obesity	Obesity	Pubtator	35937778	Associate	★☆☆☆☆ Found in Text Mining only
Oculocutaneous albinism type 2	Oculocutaneous albinism	Pubtator	23145141	Associate	★☆☆☆☆ Found in Text Mining only
Osteoporosis	Osteoporosis	Pubtator	28626757	Associate	★☆☆☆☆ Found in Text Mining only
ovarian neoplasm	Ovarian neoplasm	BEFREE	24615723		★☆☆☆☆ Found in Text Mining only
Polymyositis	Polymyositis	BEFREE	22639897		★☆☆☆☆ Found in Text Mining only
Sarcopenia	Sarcopenia	Pubtator	28626757	Associate	★☆☆☆☆ Found in Text Mining only
Scoliosis, unspecified	Scoliosis	BEFREE	27819725		★☆☆☆☆ Found in Text Mining only