ACAD9

protein-coding

acyl-CoA dehydrogenase family member 9, the group of Mitochondrial complex I assembly complex|Acyl-CoA dehydrogenase family

Gene summary

This gene encodes a member of the acyl-CoA dehydrogenase family. Members of this family of proteins localize to the mitochondria and catalyze the rate-limiting step in the beta-oxidation of fatty acyl-CoA. The encoded protein is specifically active toward palmitoyl-CoA and long-chain unsaturated substrates. Mutations in this gene cause acyl-CoA dehydrogenase family member type 9 deficiency. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Mar 2010]

MANE transcript

NM_014049.5

Inheritance

ClinVar variants

P:208U:253B:335

Top phenotype

Mitochondrial complex I deficiency, nuclear type 20

gnomAD constraint

pLI —, LoF o/e 0.54

Max pathogenic AF

—

Genomic locus

chr3:128,879,596-128,924,003

External References & Databases

Ensembl (ENSG00000177646)

Transcript & Mutation Effects

hg38 • Region Span ~44.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

acyl-CoA dehydrogenase 9 deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012624

Submitter: G2P

acyl-CoA dehydrogenase 9 deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012624

Submitter: Natera

acyl-CoA dehydrogenase 9 deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012624

Submitter: Orphanet

acyl-CoA dehydrogenase 9 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012624

Submitter: PanelApp Australia

acyl-CoA dehydrogenase 9 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012624

Submitter: Labcorp Genetics (formerly Invitae)

acyl-CoA dehydrogenase 9 deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012624

Submitter: ClinGen

Clinical Genomic Database (CGD)

Mitochondrial complex I deficiency, nuclear type 20AR

Manifestation: Biochemical; Cardiovascular; Gastrointestinal; Musculoskeletal; Neurologic

Intervention: Biochemical

Rationale: Individuals may present early in life with findings including neurologic abnormalities, cardiomyopathy, and lactic acidosis, and early institution of medical treatment (eg, with riboflavin) has been reported as leading to marked decreases in morbidity/mortality

Refs: 17564966; 21057504; 20929961; 21057504; 22499348; 25721401

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ACAD9 variants in ClinVar

9 Conditions Cataloged

not providedTotal: 912

Acyl-CoA dehydrogenase 9 deficiencyTotal: 284

not specifiedTotal: 93

Inborn genetic diseasesTotal: 88

ACAD9-related disorderTotal: 56

Mitochondrial complex I deficiencyTotal: 16

Hypertrophic cardiomyopathyTotal: 1

Possible mitochondrial disorder - nuclear genesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014049.5. 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			13 clinvar	303 clinvar	1 clinvar	317
missense	1 clinvar	44 clinvar	233 clinvar	29 clinvar		307
nonsense	11 clinvar	14 clinvar				25
start loss	1 clinvar	3 clinvar	1 clinvar			5
frameshift	26 clinvar	47 clinvar	1 clinvar	2 clinvar		76
splice donor/acceptor (+/-2bp)	4 clinvar	57 clinvar	5 clinvar			66
Total	43	165	253	334	1	796

Highest pathogenic variant AF is 0.00018028288

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 80 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014049.5	RefSeq	NP_054768.2	18	MANE Select
ENST00000308982.12	Ensembl	ENSP00000312618.7	18	MANE Select
NM_001410805.1	RefSeq	NP_001397734.1	15	Standard
ENST00000505192.5	Ensembl	ENSP00000426277.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Respiratory electron transport
The citric acid (TCA) cycle and respiratory electron transport
Metabolism
Complex I biogenesis
Respiratory electron transport, ATP synthesis by chemiosmotic coupling, and heat production by uncoupling proteins.

Biological Process

long-chain fatty acid metabolic process
mitochondrial respiratory chain complex I assembly
medium-chain fatty acid metabolic process
oxidation-reduction process

Molecular Function

fatty-acyl-CoA binding
long-chain-acyl-CoA dehydrogenase activity
protein binding
very-long-chain-acyl-CoA dehydrogenase activity
flavin adenine dinucleotide binding

Cellular Component

nucleus
mitochondrion
mitochondrial inner membrane
dendrite
mitochondrial membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000308982
Coding exons: 18
Length: 36472
Individuals with no LoFs: 125677
Homozygous LoFs: 0
Heterozygous LoFs: 71
Defined: 125748
p: 0.000282

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.179	367	357	1.03	0.0000224	4054
Missense (PolyPhen)		118	131.93	0.89441		1430
Synonymous	-0.170	147	144	1.02	0.00000954	1240
Loss of Function	2.37	17	31.3	0.543	0.00000155	379

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00058	0.00058	rare
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.00011	0.00011	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00026	0.00025	rare
South Asian	0.00026	0.00026	rare
Other	0.00066	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for mitochondrial complex I assembly (PubMed:20816094, PubMed:24158852). Has a dehydrogenase activity on palmitoyl-CoA (C16:0) and stearoyl-CoA (C18:0). It is three times more active on palmitoyl-CoA than on stearoyl-CoA. However, it does not play a primary role in long-chain fatty acid oxidation in vivo (PubMed:20816094, PubMed:24158852). Has little activity on octanoyl-CoA (C8:0), butyryl-CoA (C4:0) or isovaleryl-CoA (5:0). {ECO:0000269|PubMed:20816094, ECO:0000269|PubMed:24158852}.;

Recessive Scores

pRec: 0.223

Intolerance Scores

LoFtool: 0.168
RVIS EVS: -0.84
RVIS percentile EVS: 11.36

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.999

Gene Damage Prediction

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