ACTB

Chr 7AD

actin beta

ENSG00000075624 UniProt: P60709 OMIM: 102630

The protein is a major constituent of the contractile apparatus and one of two nonmuscle cytoskeletal actins that are ubiquitously expressed, functioning in cell motility, structure, integrity, and intercellular signaling. Loss-of-function mutations cause autosomal dominant conditions including Baraitser-Winter syndrome 1 (characterized by intellectual disability with distinctive facial features), dystonia-deafness syndrome 1, and thrombocytopenia with dysmorphic features and developmental delay. The gene is highly intolerant to loss-of-function variants, reflecting the essential role of cytoskeletal actin in cellular function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Actin is a highly conserved protein that polymerizes to produce filaments that form cross-linked networks in the cytoplasm of cells (PubMed:25255767, PubMed:29581253). Actin exists in both monomeric (G-actin) and polymeric (F-actin) forms, both forms playing key functions, such as cell motility and contraction (PubMed:29581253). In addition to their role in the cytoplasmic cytoskeleton, G- and F-actin also localize in the nucleus, and regulate gene transcription and motility and repair of damaged DNA (PubMed:29925947). Plays a role in the assembly of the gamma-tubulin ring complex (gTuRC), which regulates the minus-end nucleation of alpha-beta tubulin heterodimers that grow into microtubule protafilaments (PubMed:39321809, PubMed:38609661). Part of the ACTR1A/ACTB filament around which the dynactin complex is built (By similarity). The dynactin multiprotein complex activates the molecular motor dynein for ultra-processive transport along microtubules (By similarity)

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.235 OMIM phenotypes

Clinical Summary— ACTB

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Gene-Disease Validity (ClinGen)

Baraitser-Winter cerebrofrontofacial syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

8 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.23LOEUF

pLI 0.986

Z-score 3.32

OE 0.00 (0.00–0.23)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

5.02Z-score

OE missense 0.06 (0.04–0.10)

14 obs / 226.7 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.23)

0≤0.351.4

Missense OE?0.06 (0.04–0.10)

0≤0.61.4

Synonymous OE?1.96

0≤1.21.6

LoF obs/exp: 0 / 12.9Missense obs/exp: 14 / 226.7Syn Z: -7.44

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongACTB-related haploinsufficiency syndromeLOFAD

definitiveACTB-related Baraitser-Winter syndromeGOFAD

This gene — mechanism propensity

0.4785th %ile

GOF

0.6345th %ile

LOF

0.79top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · LOEUF 0.23

GOF1 literature citation

DN1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNDominant negative mutations in ACTB are responsible for Baraitser-Winter syndrome 1.1

GOFBaraitser-Winter, Fryns-Aftimos and cerebrofrontofacial syndrome types 1 and 3 have recently been associated with heterozygous gain-of-function mutations in one of the two ubiquitous cytoplasmic actin-encoding genes ACTB and ACTG1 that encode ÃÂ²- and ÃÂ³-actins.2

LOFIn 3 unrelated patients (XXIV, XXV, and XXVI) with a pleiotropic developmental disorder similar to BRWS1, Cuvertino et al. (2017) identified de novo heterozygous loss-of-function frameshift or nonsense mutations in the ACTB gene (102630.0008-102630.0010), consistent with haploinsufficiency.3

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References