ACADSB

protein-coding

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

Gene summary

Short/branched chain acyl-CoA dehydrogenase(ACADSB) is a member of the acyl-CoA dehydrogenase family of enzymes that catalyze the dehydrogenation of acyl-CoA derivatives in the metabolism of fatty acids or branch chained amino acids. Substrate specificity is the primary characteristic used to define members of this gene family. The ACADSB gene product has the greatest activity towards the short branched chain acyl-CoA derivative, (S)-2-methylbutyryl-CoA, but also reacts significantly with other 2-methyl branched chain substrates and with short straight chain acyl-CoAs. The cDNA encodes for a mitochondrial precursor protein which is cleaved upon mitochondrial import and predicted to yield a mature peptide of approximately 43.7-KDa. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001609.4

Inheritance

ClinVar variants

P:52U:83B:44

Top phenotype

2-methylbutyryl-CoA dehydrogenase deficiency

gnomAD constraint

pLI —, LoF o/e 0.8

Max pathogenic AF

—

Genomic locus

chr10:123,008,979-123,058,290

External References & Databases

Ensembl (ENSG00000196177)

Transcript & Mutation Effects

hg38 • Region Span ~49.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

2-methylbutyryl-CoA dehydrogenase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012392

Submitter: ClinGen

The relationship between ACADSB and 2-methylbutyryl-CoA dehydrogenase deficiency (autosomal recessive) was evaluated using the ClinGen Clinical Validity Framework as of March 12, 2019. Variants in ACADSB were first reported in humans with this deficiency as early as 2000 (Gibson, PMID: 10832746; Andresen, PMID: 11013134). The clinical significance of this disease is uncertain because almost 90% of patients are asymptomatic (Porta, 2019, PMID: 30730842). At least 15 variants have been reported in the literature (missense, nonsense, splicing). In summary, ACADSB is deﬁnitively associated with autosomal recessive 2-methylbutyryl-CoA dehydrogenase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel on March 22nd, 2019.

2-methylbutyryl-CoA dehydrogenase deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012392

Submitter: Orphanet

2-methylbutyryl-CoA dehydrogenase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012392

Submitter: Labcorp Genetics (formerly Invitae)

2-methylbutyryl-CoA dehydrogenase deficiencyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0012392

Submitter: Ambry Genetics

2-methylbutyryl-CoA dehydrogenase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012392

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

2-methylbutyryl-CoA dehydrogenase deficiencyAR

Manifestation: Biochemical

Intervention: General

Rationale: The clinical relevance of the condition is unclear, though some have stated that special attention may be necessary in situations involving potential metabolic decompensation

Refs: 10832746; 12837870; 16317551; 17883863; 17945527; 20547083; 21290185

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ACADSB variants in ClinVar

7 Conditions Cataloged

Deficiency of 2-methylbutyryl-CoA dehydrogenaseTotal: 194

not providedTotal: 34

ACADSB-related disorderTotal: 22

not specifiedTotal: 12

Inborn genetic diseasesTotal: 4

See casesTotal: 2

MicrocephalyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001609.4. 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			5 clinvar	35 clinvar	3 clinvar	43
missense	5 clinvar	7 clinvar	74 clinvar	5 clinvar	1 clinvar	92
nonsense	3 clinvar	8 clinvar				11
start loss			1 clinvar			1
frameshift	4 clinvar	10 clinvar				14
splice donor/acceptor (+/-2bp)	2 clinvar	13 clinvar	3 clinvar			18
Total	14	38	83	40	4	179

Highest pathogenic variant AF is 0.0007781455

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 29 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001609.4	RefSeq	NP_001600.1	11	MANE Select
ENST00000358776.7	Ensembl	ENSP00000357873.3	11	MANE Select
NM_001330174.3	RefSeq	NP_001317103.1	8	Standard
ENST00000368869.8	Ensembl	ENSP00000357862.4	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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

Biological Process

fatty acid metabolic process
branched-chain amino acid catabolic process
oxidation-reduction process

Molecular Function

acyl-CoA dehydrogenase activity
flavin adenine dinucleotide binding

Cellular Component

mitochondrion
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000358776
Coding exons: 11
Length: 49333
Individuals with no LoFs: 125537
Homozygous LoFs: 0
Heterozygous LoFs: 211
Defined: 125748
p: 0.000839

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0697	230	227	1.01	0.0000110	2789
Missense (PolyPhen)		89	91.567	0.97197		1143
Synonymous	0.538	78	84.3	0.925	0.00000447	818
Loss of Function	0.910	19	23.8	0.799	0.00000109	312

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0025	0.0025	notable
Latino/Admixed American	0.00063	0.00058	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.0027	0.0027	notable
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00076	0.00076	rare
South Asian	0.00020	0.00020	rare
Other	0.00082	0.00081	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Has greatest activity toward short branched chain acyl- CoA derivative such as (s)-2-methylbutyryl-CoA, isobutyryl-CoA, and 2-methylhexanoyl-CoA as well as toward short straight chain acyl-CoAs such as butyryl-CoA and hexanoyl-CoA. Can use valproyl- CoA as substrate and may play a role in controlling the metabolic flux of valproic acid in the development of toxicity of this agent.;

Recessive Scores

pRec: 0.275

Intolerance Scores

LoFtool: 0.294
RVIS EVS: -0.4
RVIS percentile EVS: 26.73

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
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