ACTN1

actinin alpha 1, the group of Actinins

Basic information

Region (hg38): 14:68874123-68979440

Links

ENSG00000072110 ∙ NCBI:87 ∙ OMIM:102575 ∙ HGNC:163 ∙ Uniprot:P12814 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• platelet-type bleeding disorder 15 (Strong), mode of inheritance: AD
• platelet-type bleeding disorder 15 (Moderate), mode of inheritance: AD
• autosomal dominant macrothrombocytopenia (Supportive), mode of inheritance: AD
• platelet-type bleeding disorder 15 (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Bleeding disorder, platelet-type, 15	AD	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	Hematologic	23434115
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

This is a list of variants' phenotypes submitted to ClinVar and linked to the ACTN1 gene.

• Platelet-type bleeding disorder 15 (2 variants)
• Macrothrombocytopenia (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ACTN1 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				62	18	80
missense	2	16	132	3	2	155
nonsense			1			1
start loss						0
frameshift						0
inframe indel		1	2			3
splice donor/acceptor (+/-2bp)						0
splice region			7	8	1	16
non coding			4	21	63	88
Total	2	17	139	86	83

Highest pathogenic variant AF is 0.00000657

Variants in ACTN1

This is a list of pathogenic ClinVar variants found in the ACTN1 region.

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

Position	Type	Phenotype	Significance	ClinVar
14-68874874-G-A		ACTN1-related disorder	Likely benign (Jun 12, 2024)
14-68874876-C-G		Thrombocytopenia;Abnormal bleeding • Platelet-type bleeding disorder 15	Likely pathogenic (Jan 03, 2022)
14-68874876-C-T			Uncertain significance (Sep 21, 2022)
14-68874877-G-A			Likely benign (Oct 13, 2022)
14-68874878-T-C			Uncertain significance (Nov 14, 2022)
14-68874899-A-G		Inborn genetic diseases	Uncertain significance (Dec 17, 2021)
14-68874921-C-T		Platelet-type bleeding disorder 15	Uncertain significance (Oct 30, 2023)
14-68874933-C-A			Uncertain significance (Jan 10, 2024)
14-68874934-G-A		ACTN1-related disorder	Likely benign (Sep 10, 2019)
14-68874936-T-A			Benign (Jan 31, 2024)
14-68874941-G-A		not specified	Benign (Jan 31, 2024)
14-68874944-G-T			Uncertain significance (Nov 08, 2022)
14-68874945-C-T			Likely benign (Nov 16, 2023)
14-68874946-C-G		ACTN1-related disorder	Uncertain significance (Aug 23, 2022)
14-68874946-C-T		Platelet-type bleeding disorder 15	Uncertain significance (-)
14-68874953-G-A			Uncertain significance (Sep 08, 2023)
14-68874964-C-G			Uncertain significance (Nov 22, 2022)
14-68874978-G-A			Uncertain significance (Jul 06, 2023)
14-68874979-T-C			Likely benign (Jun 28, 2018)
14-68874990-G-A		Platelet-type bleeding disorder 15	Conflicting classifications of pathogenicity (Apr 15, 2022)
14-68874991-G-A			Benign (Oct 28, 2022)
14-68874992-C-T		ACTN1-related disorder	Conflicting classifications of pathogenicity (Jul 23, 2022)
14-68874993-G-A			Uncertain significance (Sep 12, 2022)
14-68874999-C-T		Inborn genetic diseases	Uncertain significance (Nov 07, 2022)
14-68875001-T-C		Inborn genetic diseases	Uncertain significance (Dec 08, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ACTN1	protein_coding	protein_coding	ENST00000394419	22	105298

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.0000325	125740	0	8	125748	0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.36	359	589	0.610	0.0000381	6093
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000289	0.0000289
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.0000925	0.0000924
European (Non-Finnish)	0.0000444	0.0000439
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• 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.
• Pathway: 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);Regulation of actin cytoskeleton - Homo sapiens (human);Viral carcinogenesis - Homo sapiens (human);Leukocyte transendothelial migration - Homo sapiens (human);Arrhythmogenic Right Ventricular Cardiomyopathy;Focal Adhesion;Regulation of Actin Cytoskeleton;erk and pi-3 kinase are necessary for collagen binding in corneal epithelia;ucalpain and friends in cell spread;integrin signaling pathway;Extracellular matrix organization;Platelet degranulation ;Response to elevated platelet cytosolic Ca2+;Platelet activation, signaling and aggregation;EGFR1;Hemostasis;Syndecan interactions;Non-integrin membrane-ECM interactions;Integrin-linked kinase signaling;Regulation of cytoskeletal remodeling and cell spreading by IPP complex components;Cell-extracellular matrix interactions;Cell junction organization;Nephrin family interactions;Cell-Cell communication;Stabilization and expansion of the E-cadherin adherens junction;Signaling events mediated by focal adhesion kinase;Syndecan-4-mediated signaling events (Consensus)

Recessive Scores

• pRec: 0.316

Intolerance Scores

• loftool: 0.400
• rvis_EVS: -1.33
• rvis_percentile_EVS: 4.71

Haploinsufficiency Scores

• pHI: 0.687
• hipred: Y
• hipred_score: 0.783
• ghis: 0.630

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.774

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Actn1

Gene ontology

• Biological process: platelet degranulation;actin filament organization;platelet activation;platelet formation;platelet morphogenesis;regulation of apoptotic process;focal adhesion assembly;actin filament bundle assembly;negative regulation of cellular component movement;actin filament network formation;actin crosslink formation;platelet aggregation;postsynapse organization;positive regulation of nucleic acid-templated transcription
• Cellular component: stress fiber;ruffle;extracellular region;extracellular space;cytoplasm;cytosol;actin filament;plasma membrane;brush border;cell-cell junction;fascia adherens;focal adhesion;Z disc;platelet alpha granule lumen;pseudopodium;cell projection;extracellular exosome;glutamatergic synapse
• Molecular function: double-stranded RNA binding;integrin binding;calcium ion binding;protein binding;vinculin binding;nuclear receptor transcription coactivator activity;protein homodimerization activity;ion channel binding;actin filament binding;structural constituent of postsynapse