Human Gene Module / Chromosome 19 / ACTN4

ACTN4actinin alpha 4

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
4 / 6
Rare Variants / Common Variants
6 / 0
Aliases
ACTN4, ACTININ-4,  FSGS,  FSGS1
Associated Syndromes
-
Chromosome Band
19q13.2
Associated Disorders
-
Relevance to Autism

This gene was originally identified as an ASD candidate gene based on its enrichment in an autism-associated protein interaction module; sequencing of post-mortem brain tissue from 25 ASD cases resulted in the identification of significant non-synonymous variants in this gene with an expected false-positive rate at 0.1, confirming the involvement of this module with autism (Li et al., 2014).

Molecular Function

This gene encoded a F-actin cross-linking protein that is thought to anchor actin to a variety of intracellular structures.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to ACTN4 (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
3 Primary Integrated systems analysis reveals a molecular network underlying autism spectrum disorders Li J , et al. (2015) Yes -
4 Recent Recommendation ASD-Associated De Novo Mutations in Five Actin Regulators Show Both Shared and Distinct Defects in Dendritic Spines and Inhibitory Synapses in Cultured Hippocampal Neurons Hlushchenko I , et al. (2018) No -
5 Support - Woodbury-Smith M et al. (2022) Yes -
6 Support - Zhou X et al. (2022) Yes -
Rare Variants   (6)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.2088C>T p.Ser696%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.1174C>G p.Gln392Glu missense_variant Unknown - Unknown 25549968 Li J , et al. (2015)
c.459C>T p.Phe153%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1660A>G p.Met554Val missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1413G>A p.Glu471%3D synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.485-7T>C - splice_site_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

This gene was originally identified as an ASD candidate gene based on its enrichment in an autism-associated protein interaction module; sequencing of post-mortem brain tissue from 25 ASD cases resulted in the identification of significant non-synonymous variants in this gene with an expected false-positive rate at 0.1, confirming the involvement of this module with autism (Li et al., 2014). The non-synonymous variant in the ACTN4 gene described in this study was not reported in 1000 Genomes (as of Jan/ Feb. 2013) but was reported in dbSNP. A rare de novo missense variant that was predicted to be benign (p.Met554Val) was identified in ACTN4 in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. However, functional analysis of the ASD-associated p.Met554Val variant in transfected primary rat hippocampal neurons in Hlushchenko et al., 2018 (PMID 20123108) demonstrated that this variant reduced localization of ACTN4 protein to dendritic spines and failed to mimic the effects of overexpression of wild-type ACTN4 protein on dendritic spine morphology; these results suggested to the authors that this variant led to a loss-of-function or reduced function effect in ACTN4 protein in the regulation of dendritic spines.

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 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.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

This gene was originally identified as an ASD candidate gene based on its enrichment in an autism-associated protein interaction module; sequencing of post-mortem brain tissue from 25 ASD cases resulted in the identification of significant non-synonymous variants in this gene with an expected false-positive rate at 0.1, confirming the involvement of this module with autism (Li et al., 2014). The non-synonymous variant in the ACTN4 gene described in this study was not reported in 1000 Genomes (as of Jan/ Feb. 2013) but was reported in dbSNP. A rare de novo missense variant that was predicted to be benign (p.Met554Val) was identified in ACTN4 in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. However, functional analysis of the ASD-associated p.Met554Val variant in transfected primary rat hippocampal neurons in Hlushchenko et al., 2018 (PMID 20123108) demonstrated that this variant reduced localization of ACTN4 protein to dendritic spines and failed to mimic the effects of overexpression of wild-type ACTN4 protein on dendritic spine morphology; these results suggested to the authors that this variant led to a loss-of-function or reduced function effect in ACTN4 protein in the regulation of dendritic spines.

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

This gene was originally identified as an ASD candidate gene based on its enrichment in an autism-associated protein interaction module; sequencing of post-mortem brain tissue from 25 ASD cases resulted in the identification of significant non-synonymous variants in this gene with an expected false-positive rate at 0.1, confirming the involvement of this module with autism (Li et al., 2014). The non-synonymous variant in the ACTN4 gene described in this study was not reported in 1000 Genomes (as of Jan/ Feb. 2013) but was reported in dbSNP. A rare de novo missense variant that was predicted to be benign (p.Met554Val) was identified in ACTN4 in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. However, functional analysis of the ASD-associated p.Met554Val variant in transfected primary rat hippocampal neurons in Hlushchenko et al., 2018 (PMID 20123108) demonstrated that this variant reduced localization of ACTN4 protein to dendritic spines and failed to mimic the effects of overexpression of wild-type ACTN4 protein on dendritic spine morphology; these results suggested to the authors that this variant led to a loss-of-function or reduced function effect in ACTN4 protein in the regulation of dendritic spines.

Reports Added
[New Scoring Scheme]
7/1/2018
icon
4

Increased from to 4

Description

This gene was originally identified as an ASD candidate gene based on its enrichment in an autism-associated protein interaction module; sequencing of post-mortem brain tissue from 25 ASD cases resulted in the identification of significant non-synonymous variants in this gene with an expected false-positive rate at 0.1, confirming the involvement of this module with autism (Li et al., 2014). The non-synonymous variant in the ACTN4 gene described in this study was not reported in 1000 Genomes (as of Jan/ Feb. 2013) but was reported in dbSNP. A rare de novo missense variant that was predicted to be benign (p.Met554Val) was identified in ACTN4 in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. However, functional analysis of the ASD-associated p.Met554Val variant in transfected primary rat hippocampal neurons in Hlushchenko et al., 2018 (PMID 20123108) demonstrated that this variant reduced localization of ACTN4 protein to dendritic spines and failed to mimic the effects of overexpression of wild-type ACTN4 protein on dendritic spine morphology; these results suggested to the authors that this variant led to a loss-of-function or reduced function effect in ACTN4 protein in the regulation of dendritic spines.

Reports Added
[ASD-Associated De Novo Mutations in Five Actin Regulators Show Both Shared and Distinct Defects in Dendritic Spines and Inhibitory Synapses in Cult...2018]
Krishnan Probability Score

Score 0.55763048435824

Ranking 1332/25841 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 0.99998980455577

Ranking 455/18225 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 0.9442681274033

Ranking 16009/18665 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 0.602309969565

Ranking 82/20870 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
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
ACTN3 Human Protein Binding
ADORA2A adenosine A2a receptor Human Protein Binding 135 P29274
BMP7 bone morphogenetic protein 7 Human Protein Binding 655 A8K571
GAP43 growth associated protein 43 Rat Protein Binding 29423 P07936
MTBP Mdm2-binding protein Human Protein Binding 27085 Q96DY7
MYOZ2 myozenin 2 Human Protein Binding 51778 Q9NPC6
NOS2 nitric oxide synthase 2, inducible Mouse Protein Binding 18126 P29477
PDLIM1 PDZ and LIM domain 1 Human Protein Binding 9124 O00151
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