ACTA1

actin alpha 1, skeletal muscle, the group of Actins

Basic information

Region (hg38): 1:229430364-229434104

Previous symbols: [ "ACTA" ]

Links

ENSG00000143632 ∙ NCBI:58 ∙ OMIM:102610 ∙ HGNC:129 ∙ Uniprot:P68133 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• nemaline myopathy 3 (Strong), mode of inheritance: AR
• nemaline myopathy 3 (Definitive), mode of inheritance: Semidominant
• congenital fiber-type disproportion myopathy (Supportive), mode of inheritance: AD
• zebra body myopathy (Supportive), mode of inheritance: Unknown
• rigid spine syndrome (Supportive), mode of inheritance: AR
• severe congenital nemaline myopathy (Supportive), mode of inheritance: AR
• intermediate nemaline myopathy (Supportive), mode of inheritance: AD
• typical nemaline myopathy (Supportive), mode of inheritance: AD
• childhood-onset nemaline myopathy (Supportive), mode of inheritance: AD
• progressive scapulohumeroperoneal distal myopathy (Supportive), mode of inheritance: AD
• nemaline myopathy 3 (Strong), mode of inheritance: AR
• congenital myopathy with excess of thin filaments (Definitive), mode of inheritance: Semidominant
• congenital myopathy 2c, severe infantile, autosomal dominant (Strong), mode of inheritance: AD
• nemaline myopathy 3 (Strong), mode of inheritance: AD
• alpha-actinopathy (Definitive), mode of inheritance: AR
• alpha-actinopathy (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Congenital myopathy 2C, severe infantile, autosomal dominant; Myopathy, congenital, with fiber-type disproportion 1; Congenital myopathy 2A, severe infantile or typical, autosomal dominant; Myopathy, scapuloperoneal; Congenital myopathy 2A, typical, autosomal dominant; Congenital myopathy 2B, severe infantile, autosomal recessive	AD/AR	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Musculoskeletal; Neurologic	4952447; 9185179; 10508519; 11333380; 11558787; 15236405; 15520409; 15468086; 16427282; 17187373; 19553116; 22442437; 25182138; 25938801; 27242277

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ACTA1 gene.

• Actin accumulation myopathy (360 variants)
• not provided (126 variants)
• Congenital myopathy with fiber type disproportion (42 variants)
• Familial restrictive cardiomyopathy (30 variants)
• not specified (27 variants)
• Nemaline myopathy (11 variants)
• Progressive scapulohumeroperoneal distal myopathy (8 variants)
• Neuromuscular disease (5 variants)
• Congenital myopathy 2b, severe infantile, autosomal recessive (5 variants)
• ACTA1-related condition (5 variants)
• Congenital myopathy 2c, severe infantile, autosomal dominant (5 variants)
• ACTA1-related myopathies (4 variants)
• Inborn genetic diseases (4 variants)
• Myopathy (4 variants)
• Nemaline myopathy 3, autosomal dominant or recessive (3 variants)
• Congenital myopathy (3 variants)
• Alpha-actinopathy (3 variants)
• See cases (2 variants)
• Primary dilated cardiomyopathy (2 variants)
• - (2 variants)
• Actin accumulation myopathy;ACTA1 gene related myopathy (1 variants)
• Arthrogryposis multiplex congenita;Fetal akinesia deformation sequence 1 (1 variants)
• Neurodevelopmental delay (1 variants)
• Non-immune hydrops fetalis (1 variants)
• Congenital muscular dystrophy with rigid spine (1 variants)
• Abnormality of the musculature (1 variants)
• Actin accumulation myopathy;Congenital myopathy with fiber type disproportion;Progressive scapulohumeroperoneal distal myopathy (1 variants)
• Fetal akinesia deformation sequence (1 variants)
• Progressive scapulohumeroperoneal distal myopathy;Actin accumulation myopathy;Congenital myopathy with fiber type disproportion (1 variants)
• Actin accumulation myopathy;Progressive scapulohumeroperoneal distal myopathy;Congenital myopathy with fiber type disproportion (1 variants)
• Fetal akinesia (1 variants)
• Intranuclear rod myopathy (1 variants)
• Centronuclear myopathy (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ACTA1 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			6	55		61
missense	64	79	115			258
nonsense	4	2				6
start loss			2			2
frameshift	5	8	2			15
inframe indel	1	1	3			5
splice donor/acceptor (+/-2bp)	2	5				7
splice region			9	6	1	16
non coding			10	44	13	67
Total	76	95	138	99	13

Highest pathogenic variant AF is 0.0000131

Variants in ACTA1

This is a list of pathogenic ClinVar variants found in the ACTA1 region.

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

Position	Type	Phenotype	Significance	ClinVar
1-229431173-C-CT			Likely benign (Apr 10, 2019)
1-229431251-C-T		Congenital myopathy with fiber type disproportion • Actin accumulation myopathy • Familial restrictive cardiomyopathy	Conflicting classifications of pathogenicity (Jan 12, 2018)
1-229431433-C-T		Actin accumulation myopathy • Familial restrictive cardiomyopathy • Congenital myopathy with fiber type disproportion	Uncertain significance (Jan 12, 2018)
1-229431440-G-GC			Likely benign (Sep 05, 2018)
1-229431501-A-G		Actin accumulation myopathy	Pathogenic (Feb 04, 2022)
1-229431503-A-G		Actin accumulation myopathy	Likely pathogenic (Mar 08, 2019)
1-229431505-G-A		Familial restrictive cardiomyopathy • Congenital myopathy with fiber type disproportion • Actin accumulation myopathy	Conflicting classifications of pathogenicity (Jan 08, 2023)
1-229431506-C-A		Actin accumulation myopathy	Pathogenic/Likely pathogenic (Jul 25, 2022)
1-229431506-C-T		Actin accumulation myopathy	Uncertain significance (Jan 21, 2022)
1-229431508-T-C		Actin accumulation myopathy • Familial restrictive cardiomyopathy • Congenital myopathy with fiber type disproportion	Conflicting classifications of pathogenicity (Dec 09, 2023)
1-229431508-T-G		Nemaline myopathy	Likely pathogenic (Jun 09, 2009)
1-229431510-T-C		Actin accumulation myopathy	Likely pathogenic (Dec 21, 2020)
1-229431514-G-C			Likely pathogenic (Nov 01, 2022)
1-229431520-G-C		Familial restrictive cardiomyopathy • Actin accumulation myopathy • Congenital myopathy with fiber type disproportion	Uncertain significance (Jan 13, 2018)
1-229431524-G-T		Actin accumulation myopathy	Uncertain significance (Jul 19, 2017)
1-229431527-G-A		Actin accumulation myopathy	Likely pathogenic (Sep 05, 2021)
1-229431527-G-T		Myopathy	Uncertain significance (May 08, 2019)
1-229431529-G-A		not specified	Likely benign (Apr 27, 2021)
1-229431532-G-A			Uncertain significance (Dec 01, 2016)
1-229431535-C-T		Actin accumulation myopathy	Likely benign (Mar 17, 2022)
1-229431550-C-T		Actin accumulation myopathy	Likely benign (Aug 03, 2022)
1-229431558-T-C		Actin accumulation myopathy	Likely pathogenic (Jun 19, 2022)
1-229431558-T-G		Congenital myopathy 2c, severe infantile, autosomal dominant	Pathogenic (Jun 01, 2001)
1-229431559-C-A		Actin accumulation myopathy	Likely pathogenic (Feb 04, 2023)
1-229431562-C-G		Actin accumulation myopathy	Uncertain significance (Dec 23, 2019)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ACTA1	protein_coding	protein_coding	ENST00000366684	6	2854

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00000114	0.586	125706	0	42	125748	0.000167

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	4.53	55	261	0.211	0.0000176	2498
Missense in Polyphen		22	126.98	0.17325		1140
Synonymous	1.11	102	117	0.870	0.00000992	744
Loss of Function	0.934	11	14.9	0.739	6.45e-7	161

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000145	0.000145
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.0000931	0.0000924
European (Non-Finnish)	0.000204	0.000185
Middle Eastern	0.0000544	0.0000544
South Asian	0.000425	0.000392
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells.
• Disease: DISEASE: Nemaline myopathy 3 (NEM3) [MIM:161800]: A form of nemaline myopathy. Nemaline myopathies are muscular disorders characterized by muscle weakness of varying severity and onset, and abnormal thread-like or rod-shaped structures in muscle fibers on histologic examination. {ECO:0000269|PubMed:10508519, ECO:0000269|PubMed:11166164, ECO:0000269|PubMed:11333380, ECO:0000269|PubMed:15198992, ECO:0000269|PubMed:15236405, ECO:0000269|PubMed:15336687, ECO:0000269|PubMed:15520409, ECO:0000269|PubMed:16427282, ECO:0000269|PubMed:16945537, ECO:0000269|PubMed:17705262, ECO:0000269|PubMed:22442437, ECO:0000269|PubMed:23650303, ECO:0000269|PubMed:25938801}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Myopathy, actin, congenital, with excess of thin myofilaments (MPCETM) [MIM:161800]: A congenital muscular disorder characterized at histological level by areas of sarcoplasm devoid of normal myofibrils and mitochondria, and replaced with dense masses of thin filaments. Central cores, rods, ragged red fibers, and necrosis are absent. {ECO:0000269|PubMed:10508519}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Myopathy, congenital, with fiber-type disproportion (CFTD) [MIM:255310]: A genetically heterogeneous disorder in which there is relative hypotrophy of type 1 muscle fibers compared to type 2 fibers on skeletal muscle biopsy. However, these findings are not specific and can be found in many different myopathic and neuropathic conditions. {ECO:0000269|PubMed:15468086, ECO:0000269|PubMed:17387733}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Myopathy, scapulohumeroperoneal (SHPM) [MIM:616852]: An autosomal dominant muscular disorder characterized by progressive muscle weakness with initial scapulo-humeral-peroneal and distal distribution. Over time, muscle weakness progresses to proximal muscle groups. Clinical characteristics include scapular winging, mild lower facial weakness, foot drop due to foot eversion and dorsiflexion weakness, and selective muscle atrophy. Age at onset and disease progression are variable. {ECO:0000269|PubMed:25938801}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Myometrial Relaxation and Contraction Pathways;Fas Ligand (FasL) pathway and Stress induction of Heat Shock Proteins (HSP) regulation;Association Between Physico-Chemical Features and Toxicity Associated Pathways;Striated Muscle Contraction;erk and pi-3 kinase are necessary for collagen binding in corneal epithelia;ucalpain and friends in cell spread;integrin signaling pathway;induction of apoptosis through dr3 and dr4/5 death receptors;vegf hypoxia and angiogenesis;mcalpain and friends in cell motility;nfat and hypertrophy of the heart ;stress induction of hsp regulation;TCR;cell to cell adhesion signaling;agrin in postsynaptic differentiation;role of mal in rho-mediated activation of srf;Caspase Cascade in Apoptosis;Signaling events mediated by focal adhesion kinase;AP-1 transcription factor network;RhoA signaling pathway (Consensus)

Recessive Scores

• pRec: 0.937

Intolerance Scores

• loftool: 0.244
• rvis_EVS: -0.3
• rvis_percentile_EVS: 32.62

Haploinsufficiency Scores

• pHI: 0.906
• hipred: Y
• hipred_score: 0.802
• ghis: 0.615

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.824

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Acta1
• Phenotype: skeleton phenotype; vision/eye phenotype; 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); reproductive system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary system phenotype; homeostasis/metabolism phenotype; muscle phenotype; craniofacial phenotype; growth/size/body region phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan)

Zebrafish Information Network

• Gene name: acta1b
• Affected structure: skeletal muscle cell
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: muscle contraction;response to mechanical stimulus;response to extracellular stimulus;response to lithium ion;positive regulation of gene expression;muscle filament sliding;skeletal muscle thin filament assembly;skeletal muscle fiber adaptation;response to steroid hormone;skeletal muscle fiber development;cellular response to organonitrogen compound;mesenchyme migration
• Cellular component: stress fiber;extracellular space;cytosol;striated muscle thin filament;actin filament;actin cytoskeleton;sarcomere;lamellipodium;filopodium;cell body;extracellular exosome;blood microparticle
• Molecular function: structural constituent of cytoskeleton;protein binding;ATP binding;myosin binding;ADP binding