ACTN1
protein-codingactinin alpha 1, the group of Actinins
Gene summary
Alpha actinins belong to the spectrin gene superfamily which represents a diverse group of cytoskeletal proteins, including the alpha and beta spectrins and dystrophins. Alpha actinin is an actin-binding protein with multiple roles in different cell types. In nonmuscle cells, the cytoskeletal isoform is found along microfilament bundles and adherens-type junctions, where it is involved in binding actin to the membrane. In contrast, skeletal, cardiac, and smooth muscle isoforms are localized to the Z-disc and analogous dense bodies, where they help anchor the myofibrillar actin filaments. This gene encodes a nonmuscle, cytoskeletal, alpha actinin isoform and maps to the same site as the structurally similar erythroid beta spectrin gene. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~105.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0014078
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0014078
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0015372
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0014078
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0014078
Submitter: ClinGen
ACTN1 was first reported in relation to autosomal dominant platelet-type bleeding disorder 15 in 2013 (Kunishima et al., PMID: 23434115). Affected individuals have macrothrombocytopenia and usually have no or only mild bleeding tendency, such as epistaxis. At least 27 unique missense variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 30 probands in 8 publications (PMIDs: 23434115, 25361813, 26453073, 28562514, 27479822, 24069336, 31064749, 31237726). Variants in this gene segregated with disease in 65 additional family members. More case-level evidence is available in the literature, but the maximum score for genetic evidence has been reached. This gene-disease relationship is supported by functional alteration in patient (PMID: 25361813) and non-patient cells (PMID: 23434115). It is hypothesized that ACTN1 variants induce more stable actin filaments, thereby impairing stretching and leading to shorter and thicker fibers, however the reason why this mild phenotype is limited to platelets while ACTN1 has a ubiquitous expression is currently not well understood. In summary, ACTN1 is definitively associated with autosomal dominant platelet-type bleeding disorder 15.
Clinical Genomic Database (CGD)
Manifestation: Hematologic
Intervention: General
Rationale: 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
Comments: Individuals have been described with no or mild bleeding tendency, and it is unclear that genetic diagnosis would enable interventions or differences in management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ACTN1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001130004.2. 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 | 4 | 129 | 7 | 140 | ||
| missense | 4 | 36 | 260 | 14 | 1 | 315 |
| nonsense | 3 | 3 | ||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 9 | 9 | ||||
| Total | 4 | 36 | 276 | 143 | 8 | 467 |
Highest pathogenic variant AF is 0.000008209945
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001123476.1 | 22 | MANE Select | |
| Ensembl | ENSP00000377941.4 | 22 | MANE Select | |
| RefSeq | NP_001093.1 | 21 | Standard | |
| RefSeq | NP_001123477.1 | 21 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Focal adhesion - Homo sapiens (human)
- Adherens junction - Homo sapiens (human)
- Tight junction - Homo sapiens (human)
- Systemic lupus erythematosus - Homo sapiens (human)
- Amoebiasis - Homo sapiens (human)
Biological Process
- platelet degranulation
- actin filament organization
- platelet activation
- platelet formation
- platelet morphogenesis
Molecular Function
- double-stranded RNA binding
- integrin binding
- calcium ion binding
- protein binding
- vinculin binding
Cellular Component
- stress fiber
- ruffle
- extracellular region
- extracellular space
- cytoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000394419
- Coding exons
- 22
- Length
- 105298
- Individuals with no LoFs
- 125740
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 8
- Defined
- 125748
- p
- 0.0000318
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.36 | 359 | 589 | 0.610 | 0.0000381 | 6093 |
| Missense (PolyPhen) | 111 | 225.68 | 0.49185 | 2397 | ||
| Synonymous | 0.997 | 217 | 237 | 0.918 | 0.0000158 | 1705 |
| Loss of Function | 6.17 | 6 | 55.6 | 0.108 | 0.00000309 | 566 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.000093 | 0.000092 | rare |
| European (Non-Finnish) | 0.000044 | 0.000044 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: F-actin cross-linking protein which is thought to anchor actin to a variety of intracellular structures. This is a bundling protein.;
- Disease
- DISEASE: Bleeding disorder, platelet-type 15 (BDPLT15) [MIM:615193]: An autosomal dominant form of macrothrombocytopenia. Affected individuals usually have no or only mild bleeding tendency, such as epistaxis. Laboratory studies show decreased numbers of large platelets and anisocytosis, but the platelets show no in vitro functional abnormalities. {ECO:0000269|PubMed:23434115, ECO:0000269|PubMed:24069336}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.316
Intolerance Scores
- LoFtool
- 0.400
- RVIS EVS
- -1.33
- RVIS percentile EVS
- 4.71
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.774
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |