ACSL5

protein-coding

acyl-CoA synthetase long chain family member 5, 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 is highly expressed in uterus and spleen, and in trace amounts in normal brain, but has markedly increased levels in malignant gliomas. This gene functions in mediating fatty acid-induced glioma cell growth. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Previous symbols:

FACL5

MANE transcript

NM_203379.2

Inheritance

ClinVar variants

P:1U:87B:10

Top phenotype

Diarrhea 13

gnomAD constraint

pLI —, LoF o/e 0.51

Max pathogenic AF

—

Genomic locus

chr10:112,374,116-112,428,379

External References & Databases

Ensembl (ENSG00000197142)

Transcript & Mutation Effects

hg38 • Region Span ~54.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

diarrhea 13LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0957253

Submitter: Labcorp Genetics (formerly Invitae)

diarrhea 13MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0957253

Submitter: LiferaOmics

Genetic evidence – Published: PMID: 33191500 — One large consanguineous family with 6 affected individuals, all homozygous for NM_203379.2:c.1358C>A;p.(Thr453Lys); AR inheritance; segregation within pedigree; consistent neonatal-onset vomiting, chronic diarrhea, and FTT. Case-level points (single pedigree, shared variant) = 0.1; Functional data = 0.4; segregation = 1 PMID: 41572200 — One unrelated proband homozygous for NM_016234.4:c.1748G>A;p.(Gly583Asp); AR inheritance; consistent phenotype; no reported segregation. Case-level points = 0.1; segregation = 0; case-control = 0 Published genetic evidence total = 1.6 / 12 Genetic evidence – Current case: 1 proband with homozygous NM_016234.4:c.700+1del (canonical +1 splice donor, predicted null); neonatal vomiting, chronic diarrhea, FTT; positive consanguinity; no additional affected relatives; no segregation data; no case-control data. Case-level points (default for predicted null in AR disease) = 1.0 (AR predicted/proven null = 1.5, − 0.5 downgrade for homozygosity/consanguinity); segregation = 0; case-control = 0 Current case contribution = 1.0 / 12 Total genetic evidence (published + current) = 2.6/ 12 Experimental evidence – Published (PMID: 33191500): Functional alteration showing reduced ACSL5 enzymatic activity (Patient cells) = 1.5; biochemical function consistent with intestinal long-chain fatty acid metabolism = 0.5; intestinal expression reported = 0.5; Non-human model organism = 2.0 (PMID: 33106515) Experimental evidence total = 4.5 / 6 Overall score = 7.1 points

diarrhea 13LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0957253

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ACSL5 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 91

not providedTotal: 7

Diarrhea 13Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_203379.2. 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			1 clinvar	1 clinvar	1 clinvar	3
missense	1 clinvar		81 clinvar	6 clinvar	2 clinvar	90
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			5 clinvar			5
Total	1	0	87	7	3	98

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 81 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_203379.2	RefSeq	NP_976313.1	20	MANE Select
ENST00000354655.9	Ensembl	ENSP00000346680.4	20	MANE Select
NM_001387037.1	RefSeq	NP_001373966.1	20	Standard
NM_016234.4	RefSeq	NP_057318.2	21	Standard

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
long-chain fatty-acyl-CoA biosynthetic process

Molecular Function

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

Cellular Component

nucleus
nucleolus
mitochondrion
mitochondrial outer membrane
endoplasmic reticulum membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000356116
Coding exons: 21
Length: 54363
Individuals with no LoFs: 125703
Homozygous LoFs: 0
Heterozygous LoFs: 45
Defined: 125748
p: 0.000179

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.717	369	410	0.900	0.0000212	4841
Missense (PolyPhen)		129	161.08	0.80082		1941
Synonymous	0.960	144	159	0.903	0.00000903	1411
Loss of Function	2.96	21	41.6	0.505	0.00000191	517

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00026	0.00026	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00033	0.00033	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00017	0.00017	rare
South Asian	0.00013	0.00013	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Acyl-CoA synthetases (ACSL) activate long-chain fatty acids for both synthesis of cellular lipids, and degradation via beta-oxidation. ACSL5 may activate fatty acids from exogenous sources for the synthesis of triacylglycerol destined for intracellular storage (By similarity). Utilizes a wide range of saturated fatty acids with a preference for C16-C18 unsaturated fatty acids (By similarity). It was suggested that it may also stimulate fatty acid oxidation (By similarity). At the villus tip of the crypt-villus axis of the small intestine may sensitize epithelial cells to apoptosis specifically triggered by the death ligand TRAIL. May have a role in the survival of glioma cells. {ECO:0000250, ECO:0000269|PubMed:17681178, ECO:0000269|PubMed:18806831, ECO:0000269|PubMed:19459852}.;

Recessive Scores

pRec: 0.157

Intolerance Scores

LoFtool: 0.837
RVIS EVS: 0.27
RVIS percentile EVS: 70.64

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.791

Gene Damage Prediction

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