ACY1

Chr 3AR

aminoacylase 1

Also known as: ACY-1, ACY1D, HEL-S-5

NCBI Gene: 95 ENSG00000243989 UniProt: Q03154 OMIM: 104620

ACY1 encodes aminoacylase-1, a cytosolic zinc-binding enzyme that hydrolyzes N-acetylated and N-formylated amino acids into free amino acids and carboxylates, functioning in amino acid salvage pathways. Biallelic mutations cause aminoacylase-1 deficiency, an autosomal recessive metabolic disorder characterized by central nervous system defects and increased urinary excretion of N-acetylated amino acids. The gene shows very low constraint against loss-of-function variants (pLI near zero), consistent with the recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Aminoacylase 1 deficiencyMIM #609924

UniProtAminoacylase-1 deficiency

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · aminoacylase 1 deficiency · AR · ClinGen 2020

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.06

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.06LOEUF

pLI 0.000

Z-score 1.33

OE 0.70 (0.47–1.06)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.10Z-score

OE missense 0.98 (0.88–1.09)

237 obs / 241.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.70 (0.47–1.06)

0≤0.351.4

Missense OE?0.98 (0.88–1.09)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 16 / 22.9Missense obs/exp: 237 / 241.2Syn Z: -0.44

Background carrier burden — how many people carry a rare variant somewhere in ACY1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 87

534 rare PASS variants

Rare truncating (LoF)

1 in 820

101 rare PASS variants

Rare synonymous (reference)

1 in 380

190 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ACY1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 130	1 in 840
South Asian	~43k	1 in 78	1 in 570
Remaining (unassigned)	~30k	1 in 89	1 in 790
European (Finnish)	~27k	1 in 1,100	1 in 3,800
Admixed American	~22k	1 in 76	1 in 1,300
African / African American	~21k	1 in 65	1 in 640
East Asian	~20k	1 in 67	1 in 370
Ashkenazi Jewish	~13k	1 in 400	none seen
Middle Eastern	~2,884	1 in 72	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 14 coding exons well covered in gnomAD exomes and genomes.? see exons ↓