ACLY

protein-coding

ATP citrate lyase

Gene summary

ATP citrate lyase is the primary enzyme responsible for the synthesis of cytosolic acetyl-CoA in many tissues. The enzyme is a tetramer (relative molecular weight approximately 440,000) of apparently identical subunits. It catalyzes the formation of acetyl-CoA and oxaloacetate from citrate and CoA with a concomitant hydrolysis of ATP to ADP and phosphate. The product, acetyl-CoA, serves several important biosynthetic pathways, including lipogenesis and cholesterogenesis. In nervous tissue, ATP citrate-lyase may be involved in the biosynthesis of acetylcholine. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Dec 2014]

MANE transcript

NM_001096.3

Inheritance

—

ClinVar variants

U:147B:6

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.24

Max pathogenic AF

—

Genomic locus

chr17:41,866,917-41,930,542

External References & Databases

Ensembl (ENSG00000131473)

Transcript & Mutation Effects

hg38 • Region Span ~63.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ACLY variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 118

not providedTotal: 16

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001096.3. 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			11 clinvar	1 clinvar	4 clinvar	16
missense			127 clinvar	1 clinvar		128
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			9 clinvar			9
Total	0	0	147	2	4	153

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 121 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001096.3	RefSeq	NP_001087.2	28	MANE Select
ENST00000352035.7	Ensembl	ENSP00000253792.2	28	MANE Select
NM_001303274.1	RefSeq	NP_001290203.1	29	Standard
NM_001303275.1	RefSeq	NP_001290204.1	28	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
aclya	Danio rerio	Structure: motor neuron Quality: decreased length abnormal

Gene / Model

Organism

Observed Phenotype

aclya

Danio rerio

Structure: motor neuron

Quality: decreased length

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Citrate cycle (TCA cycle) - Homo sapiens (human)
Transfer of Acetyl Groups into Mitochondria
Glutaminolysis and Cancer
Sterol Regulatory Element-Binding Proteins (SREBP) signalling
TCA Cycle and Deficiency of Pyruvate Dehydrogenase complex (PDHc)

Biological Process

acetyl-CoA biosynthetic process
citrate metabolic process
oxaloacetate metabolic process
fatty acid biosynthetic process
cholesterol biosynthetic process

Molecular Function

ATP citrate synthase activity
protein binding
ATP binding
metal ion binding
cofactor binding

Cellular Component

extracellular region
nucleoplasm
cytosol
plasma membrane
citrate lyase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000352035
Coding exons: 28
Length: 63635
Individuals with no LoFs: 125686
Homozygous LoFs: 0
Heterozygous LoFs: 62
Defined: 125748
p: 0.000247

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.28	437	678	0.645	0.0000401	7214
Missense (PolyPhen)		117	264.89	0.4417		2799
Synonymous	1.45	241	271	0.888	0.0000181	2183
Loss of Function	5.48	15	61.3	0.245	0.00000353	668

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.0042	0.0019	notable
Finnish	0	0.0	absent
European (Non-Finnish)	0.00018	0.00018	rare
South Asian	0	0.0	absent
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: ATP-citrate synthase is the primary enzyme responsible for the synthesis of cytosolic acetyl-CoA in many tissues. Has a central role in de novo lipid synthesis. In nervous tissue it may be involved in the biosynthesis of acetylcholine. {ECO:0000269|PubMed:23932781}.;

Recessive Scores

pRec: 0.543

Intolerance Scores

LoFtool: 0.211
RVIS EVS: -0.77
RVIS percentile EVS: 13.1

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.958

Gene Damage Prediction

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