GeneBe

ACAT1

protein-coding

acetyl-CoA acetyltransferase 1

Gene summary

This gene encodes a mitochondrially localized enzyme that catalyzes the reversible formation of acetoacetyl-CoA from two molecules of acetyl-CoA. Defects in this gene are associated with 3-ketothiolase deficiency, an inborn error of isoleucine catabolism characterized by urinary excretion of 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, tiglylglycine, and butanone. [provided by RefSeq, Feb 2009]

Previous symbols:
  • ACAT

MANE transcript

NM_000019.4

Inheritance

AR

ClinVar variants

P:226U:150B:190

Top phenotype

Alpha-methylacetoacetic aciduria

gnomAD constraint

pLI —, LoF o/e 0.67

Max pathogenic AF

—

Genomic locus

chr11:108,116,695-108,148,957

External References & Databases

Ensembl (ENSG00000075239)NCBI Gene (38)OMIM (607809)HGNC:93GenCCUniProt (P24752)AlphaFoldClinVar (ACAT1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~32.3 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

beta-ketothiolase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008760

Submitter: PanelApp Australia

beta-ketothiolase deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008760

Submitter: Orphanet

beta-ketothiolase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008760

Submitter: Labcorp Genetics (formerly Invitae)

beta-ketothiolase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008760

Submitter: G2P

beta-ketothiolase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008760

Submitter: Natera

beta-ketothiolase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008760

Submitter: Ambry Genetics

beta-ketothiolase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008760

Submitter: ClinGen

Clinical Genomic Database (CGD)

Alpha-methylacetoacetic aciduriaAR

Manifestation: Biochemical; Neurologic

Intervention: Biochemical

Rationale: Individuals typically present with hypoglycemic or hyperglycemic ketoacidosis due to fasting, illnesses, and dietary changes (eg, increased protein), which can result in severe neurologic sequelae or death, and diagnosis can allow dietary and medical management (eg, protein restriction and l-carnitine supplementation) to avoid acute crises and subsequent sequelae

Refs: 4143539; 4690360; 4812006; 8103405; 8103405; 9700610; 15877211; 17236799; 18511318; 16950638; 20046049; 20157782; 21669895; 23430882; 23920042; 23958592Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ACAT1 variants in ClinVar

6 Conditions Cataloged
Deficiency of acetyl-CoA acetyltransferaseTotal: 703
not providedTotal: 65
Inborn genetic diseasesTotal: 44
not specifiedTotal: 33
ACAT1-related disorderTotal: 17
Inborn errors of metabolismTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000019.4. 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.

EffectPLPVUSLBBSum
synonymous
6
clinvar
181
clinvar
2
clinvar
 189
missense
6
clinvar
58
clinvar
134
clinvar
7
clinvar
 205
nonsense
19
clinvar
11
clinvar
1
clinvar
 31
start loss
2
clinvar
3
clinvar
 5
frameshift
43
clinvar
43
clinvar
2
clinvar
 88
splice donor/acceptor (+/-2bp)
17
clinvar
24
clinvar
7
clinvar
 48
Total871391501882566

Highest pathogenic variant AF is 0.000057621888

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 90 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000019.4RefSeqNP_000010.112MANE Select
ENST00000265838.9EnsemblENSP00000265838.412MANE Select
NM_001386677.1RefSeqNP_001373606.112Standard
NM_001386678.1RefSeqNP_001373607.19Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Tryptophan metabolism - Homo sapiens (human)
  • Pyruvate metabolism - Homo sapiens (human)
  • Butanoate metabolism - Homo sapiens (human)
  • Lysine degradation - Homo sapiens (human)
  • Propanoate metabolism - Homo sapiens (human)

Biological Process

  • liver development
  • acetyl-CoA biosynthetic process
  • isoleucine catabolic process
  • fatty acid beta-oxidation
  • brain development

Molecular Function

  • acetyl-CoA C-acetyltransferase activity
  • acetyl-CoA C-acyltransferase activity
  • carbon-carbon lyase activity
  • ligase activity, forming carbon-carbon bonds
  • enzyme binding

Cellular Component

  • mitochondrion
  • mitochondrial matrix
  • extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000265838
Coding exons
12
Length
26261
Individuals with no LoFs
125695
Homozygous LoFs
0
Heterozygous LoFs
52
Defined
125747
p
0.000207
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.9061932320.8330.00001102766
Missense (PolyPhen)6393.9420.670631136
Synonymous-0.6458577.81.090.00000393855
Loss of Function1.391420.80.6729.77e-7265

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000310.00031rare
Latino/Admixed American0.000350.00035rare
Ashkenazi Jewish0.0000990.000099rare
East Asian0.000380.00038rare
Finnish0.0000920.000092rare
European (Non-Finnish)0.000190.00018rare
South Asian0.000140.00013rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Plays a major role in ketone body metabolism.;
Disease
DISEASE: 3-ketothiolase deficiency (3KTD) [MIM:203750]: An autosomal recessive inborn error of isoleucine catabolism characterized by intermittent ketoacidotic attacks associated with unconsciousness. Some patients die during an attack or are mentally retarded. Urinary excretion of 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, triglylglycine, butanone is increased. It seems likely that the severity of this disease correlates better with the environmental or acquired factors than with the ACAT1 genotype. {ECO:0000269|PubMed:1346617, ECO:0000269|PubMed:1715688, ECO:0000269|PubMed:7728148, ECO:0000269|PubMed:9744475}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.480

Intolerance Scores

LoFtool
0.301
RVIS EVS
-0.54
RVIS percentile EVS
20.26

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.923

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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