ACTB

Gene Facts

• HGNC Symbol: ACTB (HGNC:132)
• HGNC Name: actin beta
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: No previous names found
• Alias symbols: No aliases found
• %HI: 1.03
• pLI: 1
• LOEUF: 0.19
• Cytoband: 7p22.1
• Genomic Coordinates:

  GRCh37/hg19:	chr7:5566779-5570232
  GRCh38/hg38:	chr7:5527148-5530601

• MANE Select Transcript: NM_001101.5 ENST00000646664.1
• Function: Actin is a highly conserved protein that polymerizes to produce filaments that form cross-linked networks in the cytoplasm of cells (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:299... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-28840
• ClinGen Curation ID: CCID:006615
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: No Evidence for Haploinsufficiency (0)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Related Links:
  7p22.1 region (includes ACTB)
• Last Evaluated: 02/08/2022

Haploinsufficiency (HI) Score Details

• HI Score: 0
• HI Evidence Strength: No Evidence for Haploinsufficiency

HI Disease

• syndromic intellectual disability

HI Evidence

• PUBMED: 29220674
  Cuvertino et al 2017 identified 23 overlapping deletions of 7p22.1 in 31 individuals with a similar phenotype which included developmental delay, mild to moderate intellectual disability, an increased frequency of internal organ malformation and dysmorphic facial features. All deletions contained multiple genes, however, the smallest region of overlap contained only ACTB, leading the authors to postulate that haploinsufficiency of ACTB was responsible for the shared phenotype. Variants were found to have arisen de novo in 12 individuals. In four multiplex families, the deletions segregated with the phenotype. Inheritance of the remainder of the variants was unknown. Three de novo nonsense or frameshift variants in ACTB were also found. Two of the variants, p.Ser368LeufsTer13 and p.Lys373Ter, were located in the last exon and not predicted to undergo nonsense mediated decay. The third variant, p.Leu110ArgfsTer10, is located in exon 3. This individual also had dihydropyrmidine dehydrogenase deficiency due to compound heterozygous pathogenic variants in DYPD. ACTB mRNA expression was measured in 4 individuals carrying a deletion and expression levels were consistently lower in affected individuals compared to controls. Additionally, cell migration was found to be impaired in cell lines from affected individuals. siRNA knockdown of ACTB induced similar cell migration defects suggesting the changes in cells with 7p22.1 deletions are primarily due to decreased ACTB.
• PUBMED: 31898838
  Baumann et al 2019 reported a mother and son with a 36 kb focal deletion of ACTB. Both had facial features similar to previously reported individuals with deletions including ACTB. The son also had mild developmental delay and attention deficit disorder. A third, unrelated individual was found to have a frameshift variant p.Thr297Serfs*37. This individual had global developmental delay, autism, craniosynostosis, hypospadias, patent ductus arteriosus and facial dysmorphism. The variant was not maternally inherited but paternal sample was not available.
• PUBMED: 30315159
  Latham et al 2018 reported five variants in the last two exons of ACTB in individuals with mild developmental disability, minor facial dysmorphism, microcephaly and thrombocytopenia. Two were frameshift variants in the last exon of the gene (p.Ala331Val_fs*27 and p.Ser368Leu_fs*13). Functional studies on fibroblasts carrying the p.Ala331Val_fs*27 variant showed that it did not result in nonsense mediated decay and there was translation of an abnormal protein although total protein levels were somewhat reduced. The exact mechanism of pathogenicity for these variants is unclear, however, it does not appear to be haploinsufficiency.
• PUBMED: 29274487
  Palumbo et al 2018 described an individual with developmental delay, short stature, microcephaly and dysmorphic features. Microarray testing showed a 60 kb deletion at 7p22.1 containing the genes ACTB and FBLX18. This deletion was not found in the parents or unaffected sibling.

• HI Evidence Comments: Gain of function variants in ACTB are a known cause of Baraitser-Winter cerebrofrontofacial syndrome, characterized by short stature, hypertelorism, ptosis, metopic ridging, structural brain abnormalities, mild to moderate developmental delay and variable intellectual disability. This evaluation is focused solely on the putative loss of function variants that have been described in several individuals with a phenotype that is distinct from Baraitser-Winter syndrome. Of note, many of these reported variants occur in the last exon and are not expected to undergo nonsense mediated decay; for this reason, the HI score is 0. Most of the evidence suggesting that loss of ACTB results in a clinical phenotype comes from cases involving larger deletions of the 7p22.1 region; in these cases, ACTB has been found to included in the smallest region of overlap. Please see the "7p22.1 region (includes ACTB)" curation for additional information.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity
• TS Evidence Comments: Ronzoni et al 2017 (PMID: 27866048) reported and individual with craniofacial dysmorphisms, speech and motor delay and renal anomalies. A 386 kb de novo duplication was detected at 7p22.1 encompassing ACTB, FSCN1, RNF216 and part of FBXL18. Individuals with larger overlapping deletions have been previously reported with phenotypic findings that include craniofacial dysmorphisms, speech and motor delays and heart anomalies. The authors suggest that gain of ACTB may contribute to the phenotype but no focal duplications of ACTB have been reported.