ACTB-associated syndromic thrombocytopenia

Summary

ACTB-associated syndromic thrombocytopenia (MONDO:0100433) is a disease caused by ACTB (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: ACTB (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 9

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	ACTB-associated syndromic thrombocytopenia
Mondo ID	MONDO:0100433
OMIM	620475
Orphanet	674653
UMLS	C5882677
MedGen	1851006
GARD	0026211
Is cancer (heuristic)	no

Also known as: ACTB-AST · thrombocytopenia 8, with dysmorphic features and developmental delay

Data availability: 9 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › blood platelet disease › thrombocytopenia › inherited thrombocytopenia › syndromic constitutional thrombocytopenia › ACTB-associated syndromic thrombocytopenia

Related subtypes (11): Jacobsen syndrome, platelet storage pool deficiency, Stormorken syndrome, thrombocytopenia-absent radius syndrome, radio-ulnar synostosis-amegakaryocytic thrombocytopenia syndrome, GNE myopathy, macrothrombocytopenia-lymphedema-developmental delay-facial dysmorphism-camptodactyly syndrome, thrombocytopenia 6, macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss, marcothrombocytopenia with mitral valve insufficiency, DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome

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

9 retrieved; paginated sample, class counts are floors:

3 pathogenic, 2 likely pathogenic, 2 uncertain significance, 1 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
2159436	NM_001101.5(ACTB):c.511C>T (p.Leu171Phe)	ACTB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2577405	NM_001101.5(ACTB):c.992_1008del (p.Ala331fs)	ACTB	Pathogenic	no assertion criteria provided
2577406	NM_001101.5(ACTB):c.1012_1023del (p.Ser338_Ile341del)	ACTB	Pathogenic	no assertion criteria provided
2577407	NM_001101.5(ACTB):c.1101dup (p.Ser368fs)	ACTB	Pathogenic	no assertion criteria provided
128262	NM_001101.5(ACTB):c.64G>A (p.Ala22Thr)	ACTB	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4291104	NM_001101.5(ACTB):c.1067G>A (p.Trp356Ter)	ACTB	Likely pathogenic	criteria provided, single submitter
218132	NM_001101.5(ACTB):c.1090G>A (p.Glu364Lys)	ACTB	Conflicting classifications of pathogenicity	no assertion criteria provided
3255176	NM_001101.5(ACTB):c.583G>C (p.Glu195Gln)	ACTB	Uncertain significance	criteria provided, single submitter
3392494	NM_001101.5(ACTB):c.848T>C (p.Met283Thr)	ACTB	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 5 · 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
ACTB	Strong	Autosomal dominant	ACTB-associated syndromic thrombocytopenia	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ACTB	Orphanet:2995	Baraitser-Winter cerebrofrontofacial syndrome
ACTB	Orphanet:64755	Becker nevus syndrome
ACTB	Orphanet:673556	Pseudomyogenic hemangioendothelioma
ACTB	Orphanet:674653	Actinomyopathy-associated syndromic thrombocytopenia
ACTB	Orphanet:79107	Developmental malformations-deafness-dystonia syndrome

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
ACTB	HGNC:132	ENSG00000075624	P60709	Actin, cytoplasmic 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ACTB	Actin, cytoplasmic 1	Actin is a highly conserved protein that polymerizes to produce filaments that form cross-linked networks in the cytoplasm of cells.

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)
ACTB	Other/Unknown	no		Actin, Actin_CS, Actin/actin-like_CS

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
postcentral gyrus	1
saphenous vein	1
urethra	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ACTB	295	ubiquitous	marker	urethra, postcentral gyrus, saphenous vein

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACTB	2,212

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ACTB	P60709	88

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 100. 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
Folding of actin by CCT/TriC	1	1142.0×	0.009	ACTB
Formation of annular gap junctions	1	1038.2×	0.009	ACTB
GBP-mediated host defense	1	1038.2×	0.009	ACTB
Gap junction degradation	1	951.7×	0.009	ACTB
Regulation of CDH1 Function	1	951.7×	0.009	ACTB
Cell-extracellular matrix interactions	1	671.8×	0.009	ACTB
Formation of the non-canonical BAF (ncBAF) complex	1	671.8×	0.009	ACTB
Formation of the canonical BAF (cBAF) complex	1	634.4×	0.009	ACTB
Formation of the polybromo-BAF (pBAF) complex	1	634.4×	0.009	ACTB
Formation of the embryonic stem cell BAF (esBAF) complex	1	601.0×	0.009	ACTB
Gap junction trafficking and regulation	1	475.8×	0.009	ACTB
Gap junction trafficking	1	475.8×	0.009	ACTB
Global Genome Nucleotide Excision Repair (GG-NER)	1	456.8×	0.009	ACTB
Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF)	1	456.8×	0.009	ACTB
Signaling by RAS mutants	1	423.0×	0.009	ACTB
Cooperation of Prefoldin and TriC/CCT in actin and tubulin folding	1	407.9×	0.009	ACTB
Prefoldin mediated transfer of substrate to CCT/TriC	1	393.8×	0.009	ACTB
Interaction between L1 and Ankyrins	1	368.4×	0.009	ACTB
Regulation of endogenous retroelements	1	368.4×	0.009	ACTB
Positive epigenetic regulation of rRNA expression	1	346.1×	0.009	ACTB
RHO GTPases activate IQGAPs	1	346.1×	0.009	ACTB
Parasite infection	1	346.1×	0.009	ACTB
Leishmania phagocytosis	1	346.1×	0.009	ACTB
RHO GTPases Activate WASPs and WAVEs	1	317.2×	0.009	ACTB
Signaling by high-kinase activity BRAF mutants	1	317.2×	0.009	ACTB
Sensory processing of sound	1	308.6×	0.009	ACTB
Formation of the dystrophin-glycoprotein complex (DGC)	1	308.6×	0.009	ACTB
Chaperonin-mediated protein folding	1	300.5×	0.009	ACTB
MAP2K and MAPK activation	1	285.5×	0.009	ACTB
DNA Damage Recognition in GG-NER	1	285.5×	0.009	ACTB

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
positive regulation of norepinephrine uptake	1	16852.0×	0.001	ACTB
cellular response to cytochalasin B	1	16852.0×	0.001	ACTB
regulation of norepinephrine uptake	1	8426.0×	0.001	ACTB
morphogenesis of a polarized epithelium	1	4213.0×	0.002	ACTB
regulation of transepithelial transport	1	4213.0×	0.002	ACTB
protein localization to adherens junction	1	3370.4×	0.002	ACTB
adherens junction assembly	1	1296.3×	0.004	ACTB
apical protein localization	1	991.3×	0.004	ACTB
regulation of synaptic vesicle endocytosis	1	887.0×	0.004	ACTB
regulation of G0 to G1 transition	1	674.1×	0.004	ACTB
regulation of protein localization to plasma membrane	1	648.1×	0.004	ACTB
regulation of nucleotide-excision repair	1	601.9×	0.004	ACTB
regulation of double-strand break repair	1	581.1×	0.004	ACTB
regulation of mitotic metaphase/anaphase transition	1	495.6×	0.004	ACTB
maintenance of blood-brain barrier	1	481.5×	0.004	ACTB
positive regulation of T cell differentiation	1	455.5×	0.004	ACTB
establishment or maintenance of cell polarity	1	401.2×	0.004	ACTB
cell motility	1	401.2×	0.004	ACTB
positive regulation of double-strand break repair via homologous recombination	1	383.0×	0.004	ACTB
substantia nigra development	1	366.4×	0.004	ACTB
positive regulation of myoblast differentiation	1	366.4×	0.004	ACTB
positive regulation of stem cell population maintenance	1	343.9×	0.004	ACTB
positive regulation of double-strand break repair	1	343.9×	0.004	ACTB
platelet aggregation	1	337.0×	0.004	ACTB
regulation of G1/S transition of mitotic cell cycle	1	306.4×	0.005	ACTB
negative regulation of cell differentiation	1	285.6×	0.005	ACTB
positive regulation of cell differentiation	1	267.5×	0.005	ACTB
axonogenesis	1	160.5×	0.008	ACTB
cytoskeleton organization	1	132.7×	0.009	ACTB
regulation of apoptotic process	1	83.4×	0.014	ACTB

Therapeutics

Drug target analysis

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

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
ACTB	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	ACTB

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
ACTB	21	Binding:21

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

1 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.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	ACTB

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	1	ACTB
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.