Human Gene Module / Chromosome 7 / ACTB

ACTBactin beta

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
3 / 11
Rare Variants / Common Variants
21 / 0
EAGLE Score
1
Limited Learn More
Aliases
ACTB, BRWS1,  PS1TP5BP1
Associated Syndromes
Baraitser-Winter syndrome 1
Chromosome Band
7p22.1
Associated Disorders
ASD
Genetic Category
Rare Single Gene Mutation, Syndromic
Relevance to Autism

A de novo missense variant in the ACTB gene has been identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014). Gain-of-function variants in the ACTB gene are associated with Baraitser-Winter syndrome 1 (BRWS; OMIM 243310), and while intellectual disability is frequently observed in individals with this syndrome (29/33 in Verloes et al., 2015), to date the prevalence of ASD or autistic features has not been examined. Cuvertino et al., 2017 reported 33 individuals with loss-of-function variants in the ACTB gene who presented with developmental delay, apparent intellectual disability, increased frequency of internal organ malformations, growth retardation, and a recognizable facial gestalt hat was distinct from characteristics of individuals with BRWS; five individuals from this cohort presented with autism spectrum disorder.

Molecular Function

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.

External Links
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Human
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SFARI Genomic Platforms
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Reports related to ACTB (11 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases Verloes A , et al. (2014) No -
2 Primary Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
3 Support ACTB Loss-of-Function Mutations Result in a Pleiotropic Developmental Disorder Cuvertino S , et al. (2017) No ASD
4 Support - Kwong AK et al. (2021) Yes -
5 Support - Brunet T et al. (2021) No -
6 Support - Bruno LP et al. (2021) No -
7 Support - Brea-Fernández AJ et al. (2022) No -
8 Support - Zhou X et al. (2022) Yes -
9 Support - Spataro N et al. (2023) No -
10 Support - Tamam Khalaf et al. (2024) No -
11 Support - Axel Schmidt et al. (2024) No ASD, ID
Rare Variants   (21)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 29220674 Cuvertino S , et al. (2017)
- - copy_number_loss Unknown - - 29220674 Cuvertino S , et al. (2017)
- - copy_number_loss Familial Maternal - 29220674 Cuvertino S , et al. (2017)
c.550G>T p.Asp184Tyr missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.893T>C p.Val298Ala missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1021A>G p.Ile341Val missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.294C>A p.Pro98%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.547C>T p.Arg183Trp missense_variant De novo - - 33446253 Kwong AK et al. (2021)
c.1117A>T p.Lys373Ter stop_gained De novo - - 29220674 Cuvertino S , et al. (2017)
c.1057C>T p.Gln353Ter stop_gained Unknown - - 38438125 Tamam Khalaf et al. (2024)
c.617G>A p.Arg206Gln missense_variant De novo - - 36980980 Spataro N et al. (2023)
- - copy_number_loss Familial Paternal Simplex 29220674 Cuvertino S , et al. (2017)
c.4G>T p.Asp2Tyr missense_variant De novo - Simplex 33619735 Brunet T et al. (2021)
- - copy_number_loss Familial Maternal Multiplex 29220674 Cuvertino S , et al. (2017)
c.914T>C p.Met305Thr missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.625G>A p.Val209Met missense_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.625G>A p.Val209Met missense_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
c.583G>A p.Glu195Lys missense_variant De novo - Simplex 34948243 Bruno LP et al. (2021)
c.329del p.Leu110ArgfsTer10 frameshift_variant De novo - - 29220674 Cuvertino S , et al. (2017)
c.1043C>T p.Ser348Leu missense_variant De novo - - 35322241 Brea-Fernández AJ et al. (2022)
c.1097dup p.Ser368LeufsTer13 frameshift_variant De novo - - 29220674 Cuvertino S , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

A de novo missense variant in the ACTB gene has been identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014). Gain-of-function variants in the ACTB gene are associated with Baraitser-Winter syndrome 1 (BRWS; OMIM 243310), and while intellectual disability is frequently observed in individals with this syndrome (29/33 in Verloes et al., 2015), to date the prevalence of ASD or autistic features has not been examined. Cuvertino et al., 2017 reported 33 individuals with loss-of-function variants in the ACTB gene who presented with developmental delay, apparent intellectual disability, increased frequency of internal organ malformations, growth retardation, and a recognizable facial gestalt hat was distinct from characteristics of individuals with BRWS; five individuals from this cohort presented with autism spectrum disorder.

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2021
1
icon
1

Score remained at 1

Description

A de novo missense variant in the ACTB gene has been identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014). Gain-of-function variants in the ACTB gene are associated with Baraitser-Winter syndrome 1 (BRWS; OMIM 243310), and while intellectual disability is frequently observed in individals with this syndrome (29/33 in Verloes et al., 2015), to date the prevalence of ASD or autistic features has not been examined. Cuvertino et al., 2017 reported 33 individuals with loss-of-function variants in the ACTB gene who presented with developmental delay, apparent intellectual disability, increased frequency of internal organ malformations, growth retardation, and a recognizable facial gestalt hat was distinct from characteristics of individuals with BRWS; five individuals from this cohort presented with autism spectrum disorder.

Reports Added
[Exome sequencing in paediatric patients with movement disorders2021]
1/1/2021
1
icon
1

Score remained at 1

Description

A de novo missense variant in the ACTB gene has been identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014). Gain-of-function variants in the ACTB gene are associated with Baraitser-Winter syndrome 1 (BRWS; OMIM 243310), and while intellectual disability is frequently observed in individals with this syndrome (29/33 in Verloes et al., 2015), to date the prevalence of ASD or autistic features has not been examined. Cuvertino et al., 2017 reported 33 individuals with loss-of-function variants in the ACTB gene who presented with developmental delay, apparent intellectual disability, increased frequency of internal organ malformations, growth retardation, and a recognizable facial gestalt hat was distinct from characteristics of individuals with BRWS; five individuals from this cohort presented with autism spectrum disorder.

Reports Added
[De novo variants in neurodevelopmental disorders-experiences from a tertiary care center2021]
10/1/2019
icon
1

Increased from to 1

New Scoring Scheme
Description

A de novo missense variant in the ACTB gene has been identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014). Gain-of-function variants in the ACTB gene are associated with Baraitser-Winter syndrome 1 (BRWS; OMIM 243310), and while intellectual disability is frequently observed in individals with this syndrome (29/33 in Verloes et al., 2015), to date the prevalence of ASD or autistic features has not been examined. Cuvertino et al., 2017 reported 33 individuals with loss-of-function variants in the ACTB gene who presented with developmental delay, apparent intellectual disability, increased frequency of internal organ malformations, growth retardation, and a recognizable facial gestalt hat was distinct from characteristics of individuals with BRWS; five individuals from this cohort presented with autism spectrum disorder.

Reports Added
[New Scoring Scheme]
Krishnan Probability Score

Score 0.49213507937912

Ranking 4716/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.93580321710558

Ranking 2876/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.93263132830764

Ranking 12035/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.028095777546698

Ranking 7838/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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