ACY1

protein-coding

aminoacylase 1, the group of M20 metallopeptidases

Gene summary

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. This gene is located on chromosome 3p21.1, a region reduced to homozygosity in small-cell lung cancer (SCLC), and its expression has been reported to be reduced or undetectable in SCLC cell lines and tumors. The amino acid sequence of human aminoacylase-1 is highly homologous to the porcine counterpart, and this enzyme is the first member of a new family of zinc-binding enzymes. Mutations in this gene cause aminoacylase-1 deficiency, a metabolic disorder characterized by central nervous system defects and increased urinary excretion of N-acetylated amino acids. Alternative splicing of this gene results in multiple transcript variants. Read-through transcription also exists between this gene and the upstream ABHD14A (abhydrolase domain containing 14A) gene, as represented in GeneID:100526760. A related pseudogene has been identified on chromosome 18. [provided by RefSeq, Nov 2010]

MANE transcript

NM_000666.3

Inheritance

ClinVar variants

P:20U:102B:49

Top phenotype

Aminoacylase 1 deficiency

gnomAD constraint

pLI —, LoF o/e 0.7

Max pathogenic AF

—

Genomic locus

chr3:51,983,340-51,989,197

External References & Databases

Ensembl (ENSG00000243989)

Transcript & Mutation Effects

hg38 • Region Span ~5.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

aminoacylase 1 deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012368

Submitter: ClinGen

ACY1 was first reported in relation to Autosomal Recessive Aminoacylase 1 Deficiency in 2005 (Van Coster et al., PMID: 16274666). At least 10 unique variants, most of which are missense or null, have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 14 probands in seven publications (PMIDs: 24997716, 24117009, 16465618, 17562838, 21414403, 16274666, 20480396). All of these probands share the common biochemical abnormality of organic aciduria and have confirmatory verification of deficent aminoacylase activity in fibroblasts or lymphocytes. Other phenotypes are observed in individual probands, such as psychomotor delay, hypotonia, and seizures, however the presence of asymptomatic probands indicates these phenotypes may or may not be associated with the biochemical abnormality. The mechanism for disease is biallelic loss of function, with significantly reduced or absent aminoacylase activity causing accumulation of acylated amino acids in the tissues and urine. This gene-disease association is also supported by the protein's biological function and functional studies in E. coli, demonstrating that mutant proteins have significantly impacted catalytic activity when compared to the wild-type. No animal models for this abnormality have been published at this time. In summary, ACY1 is definitively associated with autosomal recessive aminoacylase 1 deficiency. This has been repeatedly demonstrated in the clinical diagnostic setting and has been upheld over time.

aminoacylase 1 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012368

Submitter: Ambry Genetics

aminoacylase 1 deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012368

Submitter: G2P

aminoacylase 1 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012368

Submitter: Labcorp Genetics (formerly Invitae)

aminoacylase 1 deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012368

Submitter: Orphanet

aminoacylase 1 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012368

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Aminoacylase 1 deficiencyAR

Manifestation: Biochemical; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 16274666; 16465618; 17562838; 20480396; 24117009

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ACY1 variants in ClinVar

9 Conditions Cataloged

not providedTotal: 129

Inborn genetic diseasesTotal: 58

Aminoacylase 1 deficiencyTotal: 37

not specifiedTotal: 33

ACY1-related disorderTotal: 18

ABHD14A-ACY1 & ACY1-related disordersTotal: 2

ABHD14A-ACY1-related disorderTotal: 2

Intellectual disabilityTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000666.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	35 clinvar	1 clinvar	38
missense	2 clinvar	2 clinvar	94 clinvar	12 clinvar	1 clinvar	111
nonsense	2 clinvar		1 clinvar			3
start loss						0
frameshift	2 clinvar	6 clinvar	2 clinvar			10
splice donor/acceptor (+/-2bp)	2 clinvar	4 clinvar	3 clinvar			9
Total	8	12	102	47	2	171

Highest pathogenic variant AF is 0.003500814

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 89 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000666.3	RefSeq	NP_000657.1	14	MANE Select
ENST00000636358.2	Ensembl	ENSP00000490149.1	14	MANE Select
NM_001198895.2	RefSeq	NP_001185824.1	14	Standard
NM_001198896.2	RefSeq	NP_001185825.1	12	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Arginine biosynthesis - Homo sapiens (human)
Urea cycle and metabolism of amino groups
Biological oxidations
Metabolism
Methionine and cysteine metabolism

Biological Process

proteolysis
cellular amino acid metabolic process
xenobiotic metabolic process

Molecular Function

aminoacylase activity
protein binding
metallopeptidase activity
identical protein binding
metal ion binding

Cellular Component

cytosol
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000404366
Coding exons: 14
Length: 14148
Individuals with no LoFs: 125612
Homozygous LoFs: 0
Heterozygous LoFs: 136
Defined: 125748
p: 0.000541

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0951	237	241	0.983	0.0000158	2668
Missense (PolyPhen)		71	88.442	0.80278		1030
Synonymous	-0.441	98	92.6	1.06	0.00000597	812
Loss of Function	1.33	16	22.9	0.700	0.00000101	268

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0012	0.0012	notable
Latino/Admixed American	0.00032	0.00032	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.0023	0.0023	notable
Finnish	0.000096	0.000092	rare
European (Non-Finnish)	0.00046	0.00046	rare
South Asian	0.00026	0.00026	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the hydrolysis of N-acylated or N-acetylated amino acids (except L-aspartate). {ECO:0000269|PubMed:12933810}.;

Recessive Scores

pRec: 0.277

Intolerance Scores

RVIS EVS: 0.33
RVIS percentile EVS: 73.54

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.984

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium