ACTB

Chr 7AD

actin beta

Also known as: BKRNS, BNS, BRWS1, CSMH, DDS1, PS1TP5BP1, THC8

NCBI Gene: 60 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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes one of six different actin proteins. Actins are highly conserved proteins that are involved in cell motility, structure, integrity, and intercellular signaling. The encoded protein is a major constituent of the contractile apparatus and one of the two nonmuscle cytoskeletal actins that are ubiquitously expressed. Mutations in this gene cause Baraitser-Winter syndrome 1, which is characterized by intellectual disability with a distinctive facial appearance in human patients. Numerous pseudogenes of this gene have been identified throughout the human genome. [provided by RefSeq, Aug 2017]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Baraitser-Winter syndrome 1MIM #243310

Becker nevus, syndromic or isolated, somatic mosaicMIM #604919

Congenital smooth muscle hamartoma with or without hemihypertrophy, somatic mosaicMIM #620470

Dystonia-deafness syndrome 1MIM #607371

Thrombocytopenia 8, with dysmorphic features and developmental delayMIM #620475

UniProtBecker nevus syndrome

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · Baraitser-Winter cerebrofrontofacial syndrome · AD · ClinGen 2021
Definitive · Baraitser-Winter syndrome 1 · AD · G2P
Strong · developmental malformations-deafness-dystonia syndrome · AD · Genomics England PanelApp
Strong · ACTB-associated syndromic thrombocytopenia · AD · PanelApp Australia

Interpreting a novel variant

Curated mechanisms (Gene2Phenotype) include both loss of function and gain of function. Which applies is variant-dependent — do not assume a null variant is, or isn’t, the pathogenic class without checking the specific variant.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

316

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.23

LOEUF· LoF intol.

Multiple*

Mechanism· G2P

📖

GeneReview available — ACTB

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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

Background carrier burden — how many people carry a rare variant somewhere in ACTB?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 2,500

82 rare PASS variants

Rare truncating (LoF)

1 in 4,000

28 rare PASS variants

Rare synonymous (reference)

1 in 92

362 rare PASS variants

Rare missense and truncating variants are carried at similar rates in ACTB; this gene does not show strong loss-of-function constraint by this measure. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 8 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 3,700	1 in 5,100
South Asian	~43k	1 in 8,600	1 in 1,600
Remaining (unassigned)	~30k	1 in 5,000	1 in 2,700
European (Finnish)	~27k	1 in 2,200	≈ 1 in 26,000
Admixed American	~22k	1 in 1,500	≈ 1 in 4,500
African / African American	~21k	1 in 3,200	≈ 1 in 4,400
East Asian	~20k	1 in 420	1 in 2,200
Ashkenazi Jewish	~13k	≈ 1 in 4,400	≈ 1 in 13,000

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 5 coding exons well covered in gnomAD exomes and genomes.? see exons ↓