Human Gene Module / Chromosome 3 / ACY1

ACY1aminoacylase 1

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
4 / 13
Rare Variants / Common Variants
16 / 0
Aliases
ACY1, ACY-1,  ACY1D
Associated Syndromes
-
Chromosome Band
3p21.2
Associated Disorders
ID, ASD
Relevance to Autism

A homozyous missense variant in the ACY1 gene (c.1057C>T; p.Arg353Cys) was identified in a patient with ACY1 deficiency who was diagnosed with autistic syndrome (Tylki-Szymanska et al., 2010). Autistic features have also been reported in other individuals with ACY1 deficiency (Sommer et al., 2011; Alessandri et al., 2018).

Molecular Function

This gene encodes a cytosolic, homodimeric, zinc-binding enzyme that catalyzes the hydrolysis of acylated L-amino acids to L-amino acids and an acyl group, and has been postulated to function in the catabolism and salvage of acylated amino acids. Mutations in this gene cause aminoacylase-1 deficiency (ACY1D) [MIM:609924], a metabolic disorder characterized by central nervous system defects and increased urinary excretion of N-acetylated amino acids.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to ACY1 (13 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Mutations in ACY1, the gene encoding aminoacylase 1, cause a novel inborn error of metabolism Sass JO , et al. (2006) No -
2 Support Neurological findings in aminoacylase 1 deficiency Sass JO , et al. (2007) No -
3 Primary Aminoacylase 1 deficiency associated with autistic behavior Tylki-Szymanska A , et al. (2010) No ASD
4 Support The molecular basis of aminoacylase 1 deficiency Sommer A , et al. (2011) No ID, autistic features
5 Support Aminoacylase I deficiency due to ACY1 mRNA exon skipping Ferri L , et al. (2013) No ID
6 Support Isolated mild intellectual disability expands the aminoacylase 1 phenotype spectrum Alessandr MG , et al. (2014) No ID
7 Support Four years follow up of ACY1 deficient patient and pedigree study Alessandr MG , et al. (2018) No ID, autistic features
8 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
9 Support Phenotype-to-genotype approach reveals head-circumference-associated genes in an autism spectrum disorder cohort Wu H , et al. (2019) Yes Macrocephaly
10 Support - Zhou X et al. (2022) Yes -
11 Support - Cirnigliaro M et al. (2023) Yes -
12 Support - Amerh S Alqahtani et al. (2023) No Unnamed: 4
13 Support - Kirsten Furley et al. () No ASD, ID
Rare Variants   (16)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1002-6C>T - splice_region_variant De novo - - 35982159 Zhou X et al. (2022)
c.788A>C p.Asn263Thr missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.699A>C p.Glu233Asp missense_variant Unknown - - 38536866 Kirsten Furley et al. ()
c.1001_1001+5del - splice_site_variant Unknown - Unknown 24117009 Ferri L , et al. (2013)
c.1333-1G>A p.? splice_site_variant Familial Maternal Simplex 31674007 Wu H , et al. (2019)
c.699A>C p.Glu233Asp missense_variant Familial Maternal Simplex 24997716 Alessandr MG , et al. (2014)
c.1132C>T p.Arg378Trp missense_variant Familial Both parents Simplex 21414403 Sommer A , et al. (2011)
c.1133G>A p.Arg378Gln missense_variant Familial Both parents Simplex 21414403 Sommer A , et al. (2011)
c.1156C>T p.Arg386Cys missense_variant Familial Both parents Simplex 21414403 Sommer A , et al. (2011)
c.369dup p.Ala124SerfsTer23 frameshift_variant Familial Maternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.575dup p.Ser192ArgfsTer64 frameshift_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.85_88del p.Pro29ThrfsTer23 frameshift_variant Familial Maternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.575dup p.Ser192ArgfsTer64 frameshift_variant Familial Paternal Simplex 24997716 Alessandr MG , et al. (2014)
c.1057C>T p.Arg353Cys missense_variant Familial Both parents Simplex 20480396 Tylki-Szymanska A , et al. (2010)
c.575dup p.Ser192ArgfsTer64 frameshift_variant Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.575dup p.Ser192ArgfsTer64 frameshift_variant Familial Both parents Multiplex 37799141 Amerh S Alqahtani et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

A homozyous missense variant in the ACY1 gene (c.1057C>T; p.Arg353Cys) was identified in a patient with aminoacylase 1 (ACY1) deficiency who was diagnosed with autistic syndrome (Tylki-Szymanska et al., 2010). Autistic features have also been reported in other individuals with ACY1 deficiency (Sommer et al., 2011; Alessandri et al., 2018).

Score Delta: Score remained at S

criteria met
See SFARI Gene'scoring criteria
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."

10/1/2019
S
icon
S

Score remained at S

New Scoring Scheme
Description

A homozyous missense variant in the ACY1 gene (c.1057C>T; p.Arg353Cys) was identified in a patient with aminoacylase 1 (ACY1) deficiency who was diagnosed with autistic syndrome (Tylki-Szymanska et al., 2010). Autistic features have also been reported in other individuals with ACY1 deficiency (Sommer et al., 2011; Alessandri et al., 2018).

Reports Added
[Phenotype-to-genotype approach reveals head-circumference-associated genes in an autism spectrum disorder cohort.2019] [New Scoring Scheme]
7/1/2019
icon
S

Score remained at S

Description

A homozyous missense variant in the ACY1 gene (c.1057C>T; p.Arg353Cys) was identified in a patient with aminoacylase 1 (ACY1) deficiency who was diagnosed with autistic syndrome (Tylki-Szymanska et al., 2010). Autistic features have also been reported in other individuals with ACY1 deficiency (Sommer et al., 2011; Alessandri et al., 2018).

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
Krishnan Probability Score

Score 0.02448271606474

Ranking 25784/25841 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 7.6918431686347E-5

Ranking 13237/18225 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 0.83318618347846

Ranking 2936/18665 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
Larsen Cumulative Evidence Score

Score 6

Ranking 249/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score -0.040125065759701

Ranking 10062/20870 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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