ACSL4

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

Basic information

Region (hg38): X:109624243-109733403

Previous symbols: [ "FACL4", "MRX63", "MRX68" ]

Links

ENSG00000068366 ∙ NCBI:2182 ∙ OMIM:300157 ∙ HGNC:3571 ∙ Uniprot:O60488 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• non-syndromic X-linked intellectual disability (Moderate), mode of inheritance: XL
• intellectual disability, X-linked 63 (Strong), mode of inheritance: XLR
• non-syndromic X-linked intellectual disability (Supportive), mode of inheritance: XL
• intellectual disability, X-linked 63 (Strong), mode of inheritance: XL
• intellectual disability, X-linked 63 (Strong), mode of inheritance: XL
• non-syndromic X-linked intellectual disability (Definitive), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Intellectual developmental disorder, X-linked 63	XL	General	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	Neurologic	10854107; 11889465; 12525535

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ACSL4 gene.

• not provided (76 variants)
• Inborn genetic diseases (24 variants)
• Intellectual disability, X-linked 63 (20 variants)
• not specified (19 variants)
• Intellectual disability (3 variants)
• ACSL4-related condition (2 variants)
• Non-syndromic X-linked intellectual disability (2 variants)
• Autism spectrum disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ACSL4 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	11	3	16
missense		1	56	7	1	65
nonsense			1			1
start loss						0
frameshift	2	2	1			5
inframe indel			1			1
splice donor/acceptor (+/-2bp)			1			1
splice region			5	1	1	7
non coding			3	3	7	13
Total	2	3	65	21	11

Variants in ACSL4

This is a list of pathogenic ClinVar variants found in the ACSL4 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
X-109624334-G-A			Likely benign (Feb 28, 2019)
X-109624598-C-T		not specified	Likely benign (Mar 03, 2022)
X-109624611-T-C		not specified	Uncertain significance (Mar 29, 2022)
X-109624618-G-C		not specified	Uncertain significance (Jul 15, 2023)
X-109624620-G-T		not specified	Uncertain significance (Aug 28, 2023)
X-109624624-G-A		Brugada syndrome	Uncertain significance (Apr 28, 2021)
X-109624625-C-G		Brugada syndrome	Likely benign (Jul 03, 2021)
X-109624634-G-C		Brugada syndrome	Likely benign (Jan 08, 2023)
X-109624647-C-T		Brugada syndrome	Uncertain significance (Sep 22, 2022)
X-109624650-C-A		Brugada syndrome	Uncertain significance (Aug 28, 2021)
X-109624663-G-A		Brugada syndrome • KCNE5-related disorder	Uncertain significance (Feb 21, 2024)
X-109624670-C-T		Brugada syndrome	Likely benign (Mar 01, 2022)
X-109624672-C-T		Brugada syndrome	Uncertain significance (Feb 02, 2022)
X-109624675-C-A		not specified	Uncertain significance (Jan 18, 2023)
X-109624675-C-T		Brugada syndrome • not specified	Conflicting classifications of pathogenicity (Jan 17, 2024)
X-109624682-G-A		Brugada syndrome • not specified	Likely benign (Sep 22, 2023)
X-109624683-GC-TT		Brugada syndrome	Uncertain significance (Dec 01, 2021)
X-109624685-G-T		Brugada syndrome	Uncertain significance (Mar 28, 2021)
X-109624687-C-T		Brugada syndrome • not specified	Conflicting classifications of pathogenicity (Jan 22, 2024)
X-109624688-G-A		Brugada syndrome • not specified	Benign/Likely benign (Jan 17, 2024)
X-109624691-G-A		not specified	Likely benign (Nov 20, 2022)
X-109624691-G-C		not specified	Likely benign (May 11, 2023)
X-109624692-G-T		Brugada syndrome	Uncertain significance (Jan 31, 2021)
X-109624694-C-G		Brugada syndrome • not specified	Likely benign (Jul 05, 2023)
X-109624696-G-A		Brugada syndrome • not specified	Likely benign (Jun 02, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ACSL4	protein_coding	protein_coding	ENST00000340800	14	109160

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.981	0.0190	125562	0	6	125568	0.0000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.59	143	261	0.548	0.0000183	4685
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000760	0.0000615
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.000132	0.0000929
European (Non-Finnish)	0.0000371	0.0000264
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

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.
• Pathway: 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);PPAR signaling pathway - Homo sapiens (human);Ferroptosis - Homo sapiens (human);Fatty Acid Beta Oxidation;Fatty Acid Biosynthesis;Mitochondrial LC-Fatty Acid Beta-Oxidation;PPAR signaling pathway;Liver steatosis AOP;stearate biosynthesis;Metabolism of lipids;Fatty acyl-CoA biosynthesis;fatty acid activation;Leukotriene metabolism;Omega-3 fatty acid metabolism;Metabolism;Fatty acid metabolism;γ-linolenate biosynthesis;Mono-unsaturated fatty acid beta-oxidation;Omega-6 fatty acid metabolism;Di-unsaturated fatty acid beta-oxidation;Phytanic acid peroxisomal oxidation;fatty acid β-oxidation (peroxisome);icosapentaenoate biosynthesis II (metazoa);fatty acid β-oxidation;Synthesis of very long-chain fatty acyl-CoAs (Consensus)

Recessive Scores

• pRec: 0.308

Intolerance Scores

• rvis_EVS: -0.56
• rvis_percentile_EVS: 19.31

Haploinsufficiency Scores

• pHI: 0.917
• hipred: Y
• hipred_score: 0.768
• ghis: 0.629

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.872

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Acsl4
• Phenotype: normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); reproductive system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; skeleton phenotype; limbs/digits/tail phenotype; hearing/vestibular/ear phenotype; growth/size/body region phenotype; endocrine/exocrine gland phenotype; homeostasis/metabolism phenotype

Zebrafish Information Network

• Gene name: acsl4a
• Affected structure: whole organism
• Phenotype tag: abnormal
• Phenotype quality: wholly dorsalized

Gene ontology

• Biological process: long-chain fatty acid metabolic process;lipid metabolic process;response to nutrient;fatty acid transport;triglyceride biosynthetic process;long-chain fatty-acyl-CoA biosynthetic process;embryonic process involved in female pregnancy;dendritic spine development;response to interleukin-15
• Cellular component: cytoplasm;mitochondrial outer membrane;peroxisomal membrane;endoplasmic reticulum membrane;lipid droplet;membrane;integral component of membrane;neuronal cell body;mitochondria-associated endoplasmic reticulum membrane;extracellular exosome
• 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