ACADM

protein-coding

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

Gene summary

This gene encodes the medium-chain specific (C4 to C12 straight chain) acyl-Coenzyme A dehydrogenase. The homotetramer enzyme catalyzes the initial step of the mitochondrial fatty acid beta-oxidation pathway. Defects in this gene cause medium-chain acyl-CoA dehydrogenase deficiency, a disease characterized by hepatic dysfunction, fasting hypoglycemia, and encephalopathy, which can result in infantile death. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_000016.6

Inheritance

ClinVar variants

P:415U:214B:157

Top phenotype

Acyl-CoA dehydrogenase, medium chain, deficiency of

gnomAD constraint

pLI —, LoF o/e 0.8

Max pathogenic AF

—

Genomic locus

chr1:75,724,431-75,787,575

External References & Databases

Ensembl (ENSG00000117054)

Transcript & Mutation Effects

hg38 • Region Span ~63.1 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

medium chain acyl-CoA dehydrogenase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008721

Submitter: PanelApp Australia

medium chain acyl-CoA dehydrogenase deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008721

Submitter: Orphanet

medium chain acyl-CoA dehydrogenase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008721

Submitter: ClinGen

medium chain acyl-CoA dehydrogenase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008721

Submitter: G2P

medium chain acyl-CoA dehydrogenase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008721

Submitter: Labcorp Genetics (formerly Invitae)

medium chain acyl-CoA dehydrogenase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008721

Submitter: Natera

Clinical Genomic Database (CGD)

Acyl-CoA dehydrogenase, medium chain, deficiency ofAR

Manifestation: Biochemical; Musculoskeletal; Neurologic

Intervention: Biochemical

Rationale: Dietary treatment (eg, with frequent feedings in infancy, and low-fat diet for toddlers, as well as bedtime administration of uncooked cornstarch to avoid overnight hypoglycemia); In order to avoid/treat catabolism, simple oral (or IV if necessary) carbohydrates can be effective; Fasting should be avoided, as should infant formulas whose primary fat source is medium-chain triglycerides

Refs: 947635; 6402754; 6857268; 6646897; 3462713; 3944676; 3822638; 2502671; 2393404; 1361190; 8120710; 7603790; 9158144; 11349232; 11524729; 11409868; 15915086; 15832312; 19780764; 20923556; 20434380; 21239873; 20301597; 23574375

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ACADM variants in ClinVar

10 Conditions Cataloged

Medium-chain acyl-coenzyme A dehydrogenase deficiencyTotal: 922

not providedTotal: 173

Inborn genetic diseasesTotal: 61

not specifiedTotal: 57

ACADM-related disorderTotal: 29

MCADD - Medium-chain acyl-CoA dehydrogenase deficiency ? full ACADM sequencing newborn screening follow upTotal: 7

See casesTotal: 6

Epileptic spasmTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000016.6. 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	12 clinvar	150 clinvar	2 clinvar	165
missense	23 clinvar	160 clinvar	196 clinvar	3 clinvar	1 clinvar	383
nonsense	23 clinvar	35 clinvar				58
start loss	2 clinvar	3 clinvar				5
frameshift	43 clinvar	67 clinvar				110
splice donor/acceptor (+/-2bp)	17 clinvar	41 clinvar	6 clinvar	1 clinvar		65
Total	108	307	214	154	3	786

Highest pathogenic variant AF is 0.0058225337

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 124 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000016.6	RefSeq	NP_000007.1	12	MANE Select
ENST00000370841.9	Ensembl	ENSP00000359878.5	12	MANE Select
NM_001127328.3	RefSeq	NP_001120800.1	12	Standard
NM_001286042.2	RefSeq	NP_001272971.1	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

beta-Alanine metabolism - Homo sapiens (human)
Propanoate metabolism - Homo sapiens (human)
Fatty acid degradation - Homo sapiens (human)
PPAR signaling pathway - Homo sapiens (human)
Valine, leucine and isoleucine degradation - Homo sapiens (human)

Biological Process

fatty acid beta-oxidation
regulation of lipid metabolic process
carnitine metabolic process, CoA-linked
fatty acid beta-oxidation using acyl-CoA dehydrogenase
carnitine biosynthetic process

Molecular Function

acyl-CoA dehydrogenase activity
identical protein binding
flavin adenine dinucleotide binding
medium-chain-acyl-CoA dehydrogenase activity

Cellular Component

nucleus
mitochondrion
mitochondrial matrix
nuclear speck
axon

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000420607
Coding exons: 12
Length: 63225
Individuals with no LoFs: 125669
Homozygous LoFs: 0
Heterozygous LoFs: 78
Defined: 125747
p: 0.000310

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.543	205	228	0.899	0.0000114	2766
Missense (PolyPhen)		56	70.086	0.79902		844
Synonymous	0.163	70	71.8	0.976	0.00000351	798
Loss of Function	0.947	21	26.2	0.801	0.00000132	322

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00049	0.00049	rare
Latino/Admixed American	0.00017	0.00017	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00043	0.00044	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00032	0.00032	rare
South Asian	0.00052	0.00052	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Acyl-CoA dehydrogenase specific for acyl chain lengths of 4 to 16 that catalyzes the initial step of fatty acid beta- oxidation. Utilizes the electron transfer flavoprotein (ETF) as an electron acceptor to transfer electrons to the main mitochondrial respiratory chain via ETF-ubiquinone oxidoreductase (ETF dehydrogenase). {ECO:0000269|PubMed:25416781}.;
Disease: DISEASE: Acyl-CoA dehydrogenase medium-chain deficiency (ACADMD) [MIM:201450]: An inborn error of mitochondrial fatty acid beta- oxidation which causes fasting hypoglycemia, hepatic dysfunction and encephalopathy, often resulting in death in infancy. {ECO:0000269|PubMed:10767181, ECO:0000269|PubMed:11349232, ECO:0000269|PubMed:11409868, ECO:0000269|PubMed:11486912, ECO:0000269|PubMed:1363805, ECO:0000269|PubMed:1671131, ECO:0000269|PubMed:1684086, ECO:0000269|PubMed:1902818, ECO:0000269|PubMed:2251268, ECO:0000269|PubMed:2393404, ECO:0000269|PubMed:2394825, ECO:0000269|PubMed:7603790, ECO:0000269|PubMed:7929823, ECO:0000269|PubMed:8198141, ECO:0000269|PubMed:9158144, ECO:0000269|PubMed:9882619}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.722

Intolerance Scores

LoFtool: 0.155
RVIS EVS: -0.25
RVIS percentile EVS: 35.99

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.994

Gene Damage Prediction

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