Platelet-type bleeding disorder 15

Summary

Platelet-type bleeding disorder 15 (MONDO:0014078) is a disease caused by ACTN1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: ACTN1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 66

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	platelet-type bleeding disorder 15
Mondo ID	MONDO:0014078
OMIM	615193
DOID	DOID:0111053
UMLS	C3554663
MedGen	767577
GARD	0018272
Is cancer (heuristic)	no

Also known as: ACTN1 inherited bleeding disorder, platelet-type · BDPLT15 · bleeding disorder, platelet-type, 15 · inherited bleeding disorder, platelet-type caused by mutation in ACTN1 · platelet-type bleeding disorder 15

Data availability: 66 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › hemorrhagic disease › inherited bleeding disorder, platelet-type › platelet-type bleeding disorder 15

Related subtypes (27): gray platelet syndrome, primary release disorder of platelets, platelet-type von Willebrand disease, platelet-type bleeding disorder 16, platelet-type bleeding disorder 17, Ehlers-Danlos syndrome, fibronectinemic type, Bernard-Soulier syndrome, Scott syndrome, congenital thrombotic thrombocytopenic purpura, Quebec platelet disorder, platelet-type bleeding disorder 12, platelet-type bleeding disorder 10, platelet-type bleeding disorder 8, platelet-type bleeding disorder 14, platelet-type bleeding disorder 9, platelet-type bleeding disorder 11, platelet-type bleeding disorder 18, platelet-type bleeding disorder 19, platelet-type bleeding disorder 20, macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss, cytosolic phospholipase-A2 alpha deficiency associated bleeding disorder, bleeding disorder, platelet-type, 24, bleeding disorder, platelet-type, 22, bleeding disorder, platelet-type, 21, Glanzmann thrombasthenia, bleeding diathesis due to thromboxane synthesis deficiency, bleeding disorder, platelet-type, 25

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

66 retrieved; paginated sample, class counts are floors:

31 uncertain significance, 16 conflicting classifications of pathogenicity, 11 likely pathogenic, 4 pathogenic/likely pathogenic, 3 pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1684463	NM_001130004.2(ACTN1):c.384G>T (p.Trp128Cys)	ACTN1	Pathogenic	no assertion criteria provided
42028	NM_001130004.2(ACTN1):c.313G>A (p.Val105Ile)	ACTN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
42029	NM_001130004.2(ACTN1):c.94C>A (p.Gln32Lys)	ACTN1	Pathogenic	no assertion criteria provided
42031	NM_001130004.2(ACTN1):c.137G>A (p.Arg46Gln)	ACTN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
42033	NM_001130004.2(ACTN1):c.673G>A (p.Glu225Lys)	ACTN1	Pathogenic	criteria provided, multiple submitters, no conflicts
626995	NM_001130004.2(ACTN1):c.136C>T (p.Arg46Trp)	ACTN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
666546	NM_001130004.2(ACTN1):c.1348C>T (p.Arg450Cys)	ACTN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
666549	NM_001130004.1(ACTN1):c.[2156A>C;2157G>C]		Likely pathogenic	criteria provided, single submitter
1684466	NM_001130004.2(ACTN1):c.127T>A (p.Ser43Thr)	ACTN1	Likely pathogenic	no assertion criteria provided
1693577	NM_001130004.2(ACTN1):c.342A>C (p.Glu114Asp)	ACTN1	Likely pathogenic	no assertion criteria provided
1704200	NM_001130004.2(ACTN1):c.2551G>A (p.Val851Ile)	ACTN1	Likely pathogenic	criteria provided, single submitter
3393125	NM_001130004.2(ACTN1):c.388A>G (p.Ile130Val)	ACTN1	Likely pathogenic	criteria provided, single submitter
666541	NM_001130004.2(ACTN1):c.970A>G (p.Lys324Glu)	ACTN1	Likely pathogenic	criteria provided, single submitter
666543	NM_001130004.2(ACTN1):c.986A>G (p.Gln329Arg)	ACTN1	Likely pathogenic	criteria provided, single submitter
666544	NM_001130004.2(ACTN1):c.1193A>C (p.Lys398Thr)	ACTN1	Likely pathogenic	criteria provided, single submitter
666545	NM_001130004.2(ACTN1):c.1295C>T (p.Ala432Val)	ACTN1	Likely pathogenic	criteria provided, single submitter
666548	NM_001130004.2(ACTN1):c.1864C>T (p.His622Tyr)	ACTN1	Likely pathogenic	criteria provided, single submitter
988884	NM_001130004.2(ACTN1):c.2728G>C (p.Gly910Arg)	ACTN1	Likely pathogenic	criteria provided, single submitter
1306091	NM_001130004.2(ACTN1):c.2141G>A (p.Arg714His)	ACTN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1336381	NM_001130004.2(ACTN1):c.580G>A (p.Gly194Arg)	ACTN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1684409	NM_001130004.2(ACTN1):c.676+9C>T	ACTN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1684471	NM_001130004.2(ACTN1):c.2213G>A (p.Arg738Gln)	ACTN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1957245	NM_001130004.2(ACTN1):c.127T>G (p.Ser43Ala)	ACTN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2175579	NM_001130004.2(ACTN1):c.2614C>T (p.Arg872Cys)	ACTN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
42030	NM_001130004.2(ACTN1):c.2255G>A (p.Arg752Gln)	ACTN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
517137	NM_001130004.2(ACTN1):c.2201A>G (p.Gln734Arg)	ACTN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
627135	NM_001130004.2(ACTN1):c.770C>G (p.Thr257Arg)	ACTN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
627171	NM_001130004.2(ACTN1):c.1640T>C (p.Leu547Pro)	ACTN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
627175	NM_001130004.2(ACTN1):c.1959C>G (p.Ile653Met)	ACTN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
627217	NM_001130004.2(ACTN1):c.1181A>G (p.His394Arg)	ACTN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ACTN1	Definitive	Autosomal dominant	platelet-type bleeding disorder 15	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ACTN1	Orphanet:140957	Autosomal dominant macrothrombocytopenia

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ACTN1	HGNC:163	ENSG00000072110	P12814	Alpha-actinin-1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ACTN1	Alpha-actinin-1	F-actin cross-linking protein which is thought to anchor actin to a variety of intracellular structures.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ACTN1	Other/Unknown	no		Actinin_actin-bd_CS, CH_dom, Spectrin_repeat

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ascending aorta	1
blood vessel layer	1
saphenous vein	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ACTN1	292	ubiquitous	marker	blood vessel layer, saphenous vein, ascending aorta

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACTN1	3,220

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ACTN1	P12814	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 20. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Regulation of cytoskeletal remodeling and cell spreading by IPP complex components	1	1427.5×	0.008	ACTN1
RHOBTB GTPase Cycle	1	815.7×	0.008	ACTN1
Cell-extracellular matrix interactions	1	671.8×	0.008	ACTN1
Nephrin family interactions	1	475.8×	0.008	ACTN1
RHOBTB2 GTPase cycle	1	475.8×	0.008	ACTN1
Syndecan interactions	1	423.0×	0.008	ACTN1
RHOF GTPase cycle	1	259.6×	0.011	ACTN1
RHOD GTPase cycle	1	203.9×	0.012	ACTN1
Cell junction organization	1	187.2×	0.012	ACTN1
Response to elevated platelet cytosolic Ca2+	1	163.1×	0.012	ACTN1
Non-integrin membrane-ECM interactions	1	154.3×	0.012	ACTN1
Cell-Cell communication	1	137.6×	0.012	ACTN1
Platelet activation, signaling and aggregation	1	105.7×	0.015	ACTN1
Platelet degranulation	1	87.8×	0.016	ACTN1
Extracellular matrix organization	1	63.1×	0.021	ACTN1
RHO GTPase cycle	1	60.1×	0.021	ACTN1
Hemostasis	1	36.0×	0.031	ACTN1
Signaling by Rho GTPases	1	34.2×	0.031	ACTN1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	33.5×	0.031	ACTN1
Signal Transduction	1	10.2×	0.098	ACTN1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
platelet morphogenesis	1	5617.3×	0.002	ACTN1
actin filament network formation	1	1872.4×	0.002	ACTN1
muscle cell development	1	936.2×	0.003	ACTN1
platelet formation	1	702.2×	0.003	ACTN1
focal adhesion assembly	1	526.6×	0.003	ACTN1
actin filament bundle assembly	1	455.5×	0.003	ACTN1
actin filament organization	1	118.7×	0.011	ACTN1
regulation of apoptotic process	1	83.4×	0.013	ACTN1
actin cytoskeleton organization	1	79.1×	0.013	ACTN1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ACTN1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
ACTN1	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ACTN1

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ACTN1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.