ACSL4

protein-coding

acyl-CoA synthetase long chain family member 4, the group of Acyl-CoA synthetase family

Gene summary

The protein encoded by this gene is an isozyme of the long-chain fatty-acid-coenzyme A ligase family. Although differing in substrate specificity, subcellular localization, and tissue distribution, all isozymes of this family convert free long-chain fatty acids into fatty acyl-CoA esters, and thereby play a key role in lipid biosynthesis and fatty acid degradation. This isozyme preferentially utilizes arachidonate as substrate. The absence of this enzyme may contribute to the cognitive disability or Alport syndrome. Alternative splicing of this gene generates multiple transcript variants. [provided by RefSeq, Jan 2016]

Previous symbols:

FACL4
MRX63
MRX68

MANE transcript

NM_001318510.2

Inheritance

ClinVar variants

P:16U:263B:46

Top phenotype

Intellectual developmental disorder, X-linked 63

gnomAD constraint

pLI —, LoF o/e 0.12

Max pathogenic AF

—

Genomic locus

chrX:109,624,244-109,733,403

External References & Databases

Ensembl (ENSG00000068366)

Transcript & Mutation Effects

hg38 • Region Span ~109.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, X-linked 63STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010313

Submitter: G2P

intellectual developmental disorder, X-linked 63STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010313

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder, X-linked 63STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010313

Submitter: PanelApp Australia

intellectual developmental disorder, X-linked 63MODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0010313

Submitter: Ambry Genetics

non-syndromic X-linked intellectual disabilitySUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0019181

Submitter: Orphanet

non-syndromic X-linked intellectual disabilityDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0019181

Submitter: ClinGen

*ACSL4* was first reported in relation to non-syndromic X-linked intellectual disability in 2002 (Meloni et al., PMID: 11889465). Six variants, including truncating variants and missense variants resulting in loss of function, have been reported in seven unrelated families (PMIDs: 11889465, 12525535, 21584729, 26350204, 31981491, DECIPHER). Four families have multiple affected males (PMIDs: 11889465, 12525535, 21584729). Males have intellectual disability of variable severity and language impairments, without facial dysmorphism; some have autism spectrum disorder or autistic behavior. Carrier females with sequence variants or genomic deletions in *ACSL4* show a completely skewed X-inactivation and highly variable cognitive capacities, ranging from moderate or borderline intellectual disability to normal intelligence. The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by experimental evidence, including a drosophila model. *ACSL4* encodes long-chain acyl-CoA synthetase 4, an enzyme involved in fatty acid metabolism. Analysis of *ACSL4* enzymatic activity in lymphoblastoid cell lines or blood shows a marked reduction in affected individuals (PMIDs: 11889465, 12525535). In summary, there is definitive evidence supporting the relationship between *ACSL4* and non-syndromic X-linked intellectual disability. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on January 10, 2023 (SOP Version 9). This gene-disease relationship was originally evaluated on October 20, 2017 and given a Moderate classification. Curation of additional genetic evidence resulted in the classification being updated.

non-syndromic X-linked intellectual disabilityMODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0019181

Submitter: Illumina

Clinical Genomic Database (CGD)

Intellectual developmental disorder, X-linked 63XL

Manifestation: 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: 10854107; 11889465; 12525535

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ACSL4 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 131

Inborn genetic diseasesTotal: 50

Intellectual disability, X-linked 63Total: 41

not specifiedTotal: 29

ACSL4-related disorderTotal: 13

Intellectual disabilityTotal: 4

Non-syndromic X-linked intellectual disabilityTotal: 2

Autism spectrum disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001318510.2. 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			26 clinvar	17 clinvar	4 clinvar	47
missense	1 clinvar	4 clinvar	192 clinvar	24 clinvar	1 clinvar	222
nonsense	1 clinvar		13 clinvar			14
start loss						0
frameshift	3 clinvar	5 clinvar	4 clinvar			12
splice donor/acceptor (+/-2bp)	1 clinvar	1 clinvar	28 clinvar			30
Total	6	10	263	41	5	325

Highest pathogenic variant AF is 0.0000018419463

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 61 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001318510.2	RefSeq	NP_001305439.1	14	MANE Select
ENST00000672401.1	Ensembl	ENSP00000500273.1	14	MANE Select
NM_001318509.2	RefSeq	NP_001305438.1	14	Standard
NM_001437245.1	RefSeq	NP_001424174.1	14	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
acsl4a	Danio rerio	Structure: whole organism Quality: wholly dorsalized abnormal

Gene / Model

Organism

Observed Phenotype

acsl4a

Danio rerio

Structure: whole organism

Quality: wholly dorsalized

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Adipocytokine signaling pathway - Homo sapiens (human)
Peroxisome - Homo sapiens (human)
Thermogenesis - Homo sapiens (human)
Fatty acid degradation - Homo sapiens (human)
Fatty acid biosynthesis - Homo sapiens (human)

Biological Process

long-chain fatty acid metabolic process
lipid metabolic process
response to nutrient
fatty acid transport
triglyceride biosynthetic process

Molecular Function

long-chain fatty acid-CoA ligase activity
ATP binding
very long-chain fatty acid-CoA ligase activity
arachidonate-CoA ligase activity
decanoate-CoA ligase activity

Cellular Component

cytoplasm
mitochondrial outer membrane
peroxisomal membrane
endoplasmic reticulum membrane
lipid droplet

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000340800
Coding exons: 14
Length: 109160
Individuals with no LoFs: 125562
Homozygous LoFs: 0
Heterozygous LoFs: 6
Defined: 125568
p: 0.0000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.59	143	261	0.548	0.0000183	4685
Missense (PolyPhen)		50	119.64	0.41793		2100
Synonymous	0.0693	90	90.8	0.991	0.00000642	1346
Loss of Function	4.11	3	25.3	0.118	0.00000201	448

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000076	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.00013	0.000093	rare
European (Non-Finnish)	0.000037	0.000026	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Activation of long-chain fatty acids for both synthesis of cellular lipids, and degradation via beta-oxidation. Preferentially uses arachidonate and eicosapentaenoate as substrates.;
Disease: DISEASE: Mental retardation, X-linked 63 (MRX63) [MIM:300387]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non- syndromic X-linked mental retardation, while syndromic mental retardation presents with associated physical, neurological and/or psychiatric manifestations. {ECO:0000269|PubMed:11889465}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Alport syndrome with mental retardation, midface hypoplasia and elliptocytosis (ATS-MR) [MIM:300194]: A X-linked contiguous gene deletion syndrome characterized by glomerulonephritis, sensorineural hearing loss, mental retardation, midface hypoplasia and elliptocytosis. {ECO:0000269|PubMed:9480748}. Note=The gene represented in this entry may be involved in disease pathogenesis.;

Recessive Scores

pRec: 0.308

Intolerance Scores

RVIS EVS: -0.56
RVIS percentile EVS: 19.31

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.872

Gene Damage Prediction

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