ACADS

protein-coding

acyl-CoA dehydrogenase short chain, the group of Acyl-CoA dehydrogenase family

Gene summary

This gene encodes a tetrameric mitochondrial flavoprotein, which is a member of the acyl-CoA dehydrogenase family. This enzyme catalyzes the initial step of the mitochondrial fatty acid beta-oxidation pathway. Mutations in this gene have been associated with short-chain acyl-CoA dehydrogenase (SCAD) deficiency. Alternative splicing results in two variants which encode different isoforms. [provided by RefSeq, Oct 2014]

MANE transcript

NM_000017.4

Inheritance

ClinVar variants

P:117U:166B:89

Top phenotype

Acyl-CoA dehydrogenase, short-chain, deficiency of

gnomAD constraint

pLI —, LoF o/e 0.59

Max pathogenic AF

—

Genomic locus

chr12:120,725,774-120,740,008

External References & Databases

Ensembl (ENSG00000122971)

Transcript & Mutation Effects

hg38 • Region Span ~14.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

short chain acyl-CoA dehydrogenase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008722

Submitter: Ambry Genetics

short chain acyl-CoA dehydrogenase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008722

Submitter: ClinGen

short chain acyl-CoA dehydrogenase deficiencyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0008722

Submitter: PanelApp Australia

short chain acyl-CoA dehydrogenase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008722

Submitter: Labcorp Genetics (formerly Invitae)

short chain acyl-CoA dehydrogenase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008722

Submitter: G2P

short chain acyl-CoA dehydrogenase deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008722

Submitter: Orphanet

Clinical Genomic Database (CGD)

Acyl-CoA dehydrogenase, short-chain, deficiency ofAR

Manifestation: Biochemical;Musculoskeletal; Neurologic

Intervention: Biochemical

Rationale: Clinical manifestations range from infantile acute acidosis and muscle weakness to chronic adult myopathy, and in the infantile forms, medical/dietary therapy (eg, IV glucose/carnitine in the initial phase, and low-fat, diet with MCT oil and carnitine and riboflavin, as well as avoidance of fasting) can be effective

Refs: 3571488; 3335634; 2808706; 7776094; 9266373; 9499414; 9578969; 9932958; 11134486; 11524729; 18523805; 18054510; 20376488; 20429031; 21325261; 21500142

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ACADS variants in ClinVar

7 Conditions Cataloged

Deficiency of butyryl-CoA dehydrogenaseTotal: 415

not providedTotal: 113

ACADS-related disorderTotal: 43

not specifiedTotal: 36

Inborn genetic diseasesTotal: 7

See casesTotal: 3

Type 2 diabetes mellitusTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000017.4. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	80 clinvar	3 clinvar	86
missense	5 clinvar	50 clinvar	160 clinvar	6 clinvar		221
nonsense	6 clinvar	6 clinvar	1 clinvar			13
start loss	1 clinvar	2 clinvar				3
frameshift	9 clinvar	22 clinvar	2 clinvar			33
splice donor/acceptor (+/-2bp)	2 clinvar	14 clinvar				16
Total	23	94	166	86	3	372

Highest pathogenic variant AF is 0.0005020338

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 42 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000017.4	RefSeq	NP_000008.1	10	MANE Select
ENST00000242592.9	Ensembl	ENSP00000242592.4	10	MANE Select
NM_001302554.2	RefSeq	NP_001289483.1	10	Standard
ENST00000411593.2	Ensembl	ENSP00000401045.2	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Butanoate metabolism - Homo sapiens (human)
Fatty acid degradation - Homo sapiens (human)
Valine, leucine and isoleucine degradation - Homo sapiens (human)
Long chain acyl-CoA dehydrogenase deficiency (LCAD)
3-Methylglutaconic Aciduria Type I

Biological Process

fatty acid beta-oxidation
fatty acid beta-oxidation using acyl-CoA dehydrogenase
butyrate catabolic process

Molecular Function

acyl-CoA dehydrogenase activity
butyryl-CoA dehydrogenase activity
flavin adenine dinucleotide binding

Cellular Component

nucleus
nucleoplasm
mitochondrion
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000242592
Coding exons: 10
Length: 14274
Individuals with no LoFs: 125708
Homozygous LoFs: 0
Heterozygous LoFs: 40
Defined: 125748
p: 0.000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.584	239	266	0.899	0.0000182	2650
Missense (PolyPhen)		117	131.42	0.89029		1266
Synonymous	0.319	113	117	0.963	0.00000936	845
Loss of Function	1.74	12	20.5	0.586	9.92e-7	223

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00038	0.00037	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000055	0.000054	rare
Finnish	0.00023	0.00023	rare
European (Non-Finnish)	0.00014	0.00014	rare
South Asian	0.00026	0.00026	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Introduces a double bond at position 2 in saturated acyl-CoA's of short chain length, i.e. less than 6 carbon atoms. {ECO:0000250|UniProtKB:P15651}.;
Disease: DISEASE: Acyl-CoA dehydrogenase short-chain deficiency (ACADSD) [MIM:201470]: An inborn error of mitochondrial fatty acid beta- oxidation resulting in acute acidosis and muscle weakness in infants, and a form of lipid-storage myopathy in adults. {ECO:0000269|PubMed:11134486, ECO:0000269|PubMed:1692038, ECO:0000269|PubMed:9499414}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.526

Intolerance Scores

LoFtool: 0.196
RVIS EVS: -0.2
RVIS percentile EVS: 39.11

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.709

Gene Damage Prediction

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