Human Gene Module / Chromosome 7 / ACTL6B

ACTL6Bactin like 6B

Score
S
Syndromic Syndromic
Autism Reports / Total Reports
1 / 8
Rare Variants / Common Variants
20 / 0
Aliases
ACTL6B, ACTL6,  BAF53B,  arpNalpha
Associated Syndromes
Rett syndrome
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
7q22.1
Associated Disorders
EPS, ASD, EP
Relevance to Autism

Bell et al., 2019 demonstrated that individuals harboring biallelic mutations in the ACTL6B gene presented with a neurodevelopmental disorder characterized by global developmental delay, epileptic encephalopathy, axial hypotonia, and spasticity, whereas individuals with de novo heterozygous missense variants in the same gene presented with intellectual disability, developmental delay, delayed or absent speech, ambulation deficits, hypotonia, autism or autistic features, Rett-like stereotypies such as handwringing, and minor facial dysmorphisms (wide mouth, diastema, bulbous nose). Homozygous variants in the ACTL6B gene had previously been identified in three individuals from two families presenting with severe developmental and epileptic encephalopathy in Fichera et al., 2019, as well as in two siblings presenting with intellectual disability, seizures, and autistic behaviors (Karaca et al., 2015) and a female patient diagnosed with atypical Rett syndrome (Sajan et al., 2017). A postzygotic mosaic coding-synonymous variant that was predicted to create a new exonic splicing site in the ACTL6B gene was observed in an ASD proband from the Simons Simplex Collection in Krupp et al., 2017.

Molecular Function

The protein encoded by this gene is a member of a family of actin-related proteins (ARPs) which share significant amino acid sequence identity to conventional actins. Both actins and ARPs have an actin fold, which is an ATP-binding cleft, as a common feature. The ARPs are involved in diverse cellular processes, including vesicular transport, spindle orientation, nuclear migration and chromatin remodeling. This gene encodes a subunit of the BAF (BRG1/brm-associated factor) complex in mammals, which is functionally related to SWI/SNF complex in S. cerevisiae and Drosophila; the latter is thought to facilitate transcriptional activation of specific genes by antagonizing chromatin-mediated transcriptional repression. This subunit may be involved in the regulation of genes by structural modulation of their chromatin, specifically in the brain.

Reports related to ACTL6B (8 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease. Karaca E , et al. (2015) No Autistic behavior, microcephaly
2 Support Enrichment of mutations in chromatin regulators in people with Rett syndrome lacking mutations in MECP2. Sajan SA , et al. (2016) No -
3 Support Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder. Krupp DR , et al. (2017) Yes -
4 Support Mutations in ACTL6B, coding for a subunit of the neuron-specific chromatin remodeling complex nBAF, cause early onset severe developmental and epil... Fichera M , et al. (2019) No -
5 Primary Mutations in ACTL6B Cause Neurodevelopmental Deficits and Epilepsy and Lead to Loss of Dendrites in Human Neurons. Bell S , et al. (2019) No Epilepsy/seizures, ASD or autistic features
6 Support Variantrecurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense v... Lecoquierre F , et al. (2019) No -
7 Support Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population. Monies D , et al. (2019) No Hypertonia, GERD
8 Support Pathogenic homozygous variations in ACTL6B cause DECAM syndrome: Developmental delay, Epileptic encephalopathy, Cerebral Atrophy, and abnormal Myel... Yksel Z , et al. (2019) No -
Rare Variants   (20)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.230A>G p.Asp77Gly missense_variant De novo - - 31031012 Bell S , et al. (2019)
c.1027G>A p.Gly343Arg missense_variant De novo - - 31031012 Bell S , et al. (2019)
c.360C>T p.(=) synonymous_variant De novo - Simplex 28867142 Krupp DR , et al. (2017)
c.1027G>A p.Gly343Arg missense_variant Unknown Not maternal Multi-generational 31036916 Lecoquierre F , et al. (2019)
c.[852C>G];[740G>A] p.[Tyr284Ter];[Trp247Ter] stop_gained;stop_gained Familial - Simplex 31031012 Bell S , et al. (2019)
c.[1231C>T];[669+1G>A] p.[Gln411Ter];[?] stop_gained;splice_site_variant Familial - Simplex 31031012 Bell S , et al. (2019)
c.[389G>A];[556C>T] p.[Arg130Gln];[Gln186Ter] missense_variant;stop_gained Familial - Simplex 31031012 Bell S , et al. (2019)
c.[724C>T];[617T>C] p.[Gln242Ter];[Leu206Pro] stop_gained;missense_variant Familial - Simplex 31031012 Bell S , et al. (2019)
c.[289C>T];[289C>T] p.[Arg97Ter];[Arg97Ter] stop_gained;stop_gained Familial Both parents Simplex 31031012 Bell S , et al. (2019)
c.[820C>T];[820C>T] p.[Gln274Ter];[Gln274Ter] stop_gained;stop_gained Familial Both parents Multiplex 30656450 Fichera M , et al. (2019)
c.[695delC];[1275C>A] p.[Pro232GlnfsTer24];[Cys425Ter] frameshift_variant;stop_gained Familial - Multiplex 31031012 Bell S , et al. (2019)
c.[1045G>A];[1045G>A] p.[Gly349Ser];[Gly349Ser] missense_variant;missense_variant Familial Both parents Multiplex 31031012 Bell S , et al. (2019)
c.[893G>A];[893G>A] p.[Arg298Gln];[Arg298Gln] missense_variant;missense_variant Familial Both parents Multiplex 26539891 Karaca E , et al. (2015)
c.[1045G>A];[1045G>A] p.[Gly349Ser];[Gly349Ser] missense_variant;missense_variant Familial Both parents Multiplex 30656450 Fichera M , et al. (2019)
c.[441_443delCTT];[441_443delCTT] p.[Phe147del];[Phe147del] inframe_deletion;inframe_deletion Familial Both parents Unknown 31031012 Bell S , et al. (2019)
c.[1279del];[1279del] p.[Ter427AspextTer33];[Ter427AspextTer33] frameshift_variant;frameshift_variant Familial Both parents Simplex 31031012 Bell S , et al. (2019)
c.[999T>A];[999T>A] p.[Cys333Ter];[Cys333Ter] stop_gained;stop_gained Familial Both parents Not simplex (positive family history) 31130284 Monies D , et al. (2019)
c.[1279del];[1279del] p.[Ter427AspextTer33];[Ter427AspextTer33] frameshift_variant;frameshift_variant Familial Both parents Multiplex 31031012 Bell S , et al. (2019)
c.[1279delT];[1279delT] p.[Ter427AspextTer32];[Ter427AspextTer32] frameshift_variant;frameshift_variant Familial Both parents Simplex 27171548 Sajan SA , et al. (2016)
c.[1261_1275del];[1261_1275del] p.[Val421_Cys425del];[Val421_Cys425del] inframe_deletion;inframe_deletion Familial Both parents Extended multiplex 31134736 Yksel Z , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

Bell et al., 2019 demonstrated that individuals harboring biallelic mutations in the ACTL6B gene presented with a neurodevelopmental disorder characterized by global developmental delay, epileptic encephalopathy, axial hypotonia, and spasticity, whereas individuals with de novo heterozygous missense variants in the same gene presented with intellectual disability, developmental delay, delayed or absent speech, ambulation deficits, hypotonia, autism or autistic features, Rett-like stereotypies such as handwringing, and minor facial dysmorphisms (wide mouth, diastema, bulbous nose). Homozygous variants in the ACTL6B gene had previously been identified in three individuals from two families presenting with severe developmental and epileptic encephalopathy in Fichera et al., 2019, as well as in two siblings presenting with intellectual disability, seizures, and autistic behaviors (Karaca et al., 2015) and a female patient diagnosed with atypical Rett syndrome (Sajan et al., 2017). A postzygotic mosaic coding-synonymous variant that was predicted to create a new exonic splicing site in the ACTL6B gene was observed in an ASD proband from the Simons Simplex Collection in Krupp et al., 2017.

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."

7/1/2019
S

Initial score established: S

Description

Bell et al., 2019 demonstrated that individuals harboring biallelic mutations in the ACTL6B gene presented with a neurodevelopmental disorder characterized by global developmental delay, epileptic encephalopathy, axial hypotonia, and spasticity, whereas individuals with de novo heterozygous missense variants in the same gene presented with intellectual disability, developmental delay, delayed or absent speech, ambulation deficits, hypotonia, autism or autistic features, Rett-like stereotypies such as handwringing, and minor facial dysmorphisms (wide mouth, diastema, bulbous nose). Homozygous variants in the ACTL6B gene had previously been identified in three individuals from two families presenting with severe developmental and epileptic encephalopathy in Fichera et al., 2019, as well as in two siblings presenting with intellectual disability, seizures, and autistic behaviors (Karaca et al., 2015) and a female patient diagnosed with atypical Rett syndrome (Sajan et al., 2017). A postzygotic mosaic coding-synonymous variant that was predicted to create a new exonic splicing site in the ACTL6B gene was observed in an ASD proband from the Simons Simplex Collection in Krupp et al., 2017.

Krishnan Probability Score

Score 0.75653407573024

Ranking 32/25841 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.
ExAC Score

Score 0.98713069486597

Ranking 1917/18225 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
Sanders TADA Score

Score 0.9303064247357

Ranking 11394/18665 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).
Zhang D Score

Score 0.23506461212265

Ranking 3688/20870 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.
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