ACSF3

protein-coding

acyl-CoA synthetase family member 3, the group of Acyl-CoA synthetase family

Gene summary

This gene encodes a member of the acyl-CoA synthetase family of enzymes that activate fatty acids by catalyzing the formation of a thioester linkage between fatty acids and coenzyme A. The encoded protein is localized to mitochondria, has high specificity for malonate and methylmalonate and possesses malonyl-CoA synthetase activity. Mutations in this gene are a cause of combined malonic and methylmalonic aciduria. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Sep 2013]

MANE transcript

NM_001243279.3

Inheritance

AR, AD

ClinVar variants

P:200U:282B:368

Top phenotype

Combined malonic and methylmalonic aciduria

gnomAD constraint

pLI —, LoF o/e 1.35

Max pathogenic AF

—

Genomic locus

chr16:89,088,375-89,164,121

External References & Databases

Ensembl (ENSG00000176715)

Transcript & Mutation Effects

hg38 • Region Span ~75.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

combined malonic and methylmalonic acidemiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013661

Submitter: Natera

combined malonic and methylmalonic acidemiaMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013661

Submitter: PanelApp Australia

combined malonic and methylmalonic acidemiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013661

Submitter: Orphanet

combined malonic and methylmalonic acidemiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013661

Submitter: Labcorp Genetics (formerly Invitae)

combined malonic and methylmalonic acidemiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013661

Submitter: ClinGen

ACSF3 was first reported in relation to autosomal recessive combined malonic and methylmalonic acidemia (CMAMMA) in 2011 (Alfares et al., PMID: 21785126), with cases identifying the causal enzyme, malonyl coenzyme A decarboxylase, having been reported since 1984 (Brown et al., PMID: 6145813). At least 19 unique variants (e.g. missense, in-frame indel, nonsense, frameshift, etc) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and some experimental data. Variants in this gene have been reported in at least 26 probands in six publications (PMIDs: 21785126, 26915364, 30740739, 26827111, 27604308, 21841779). All of these probands show evidence of the biochemical abnormalities characteristic of this disorder, however many of them do not demonstrate any additional phenotypic abnormalities. Additionally, many of these variants have high population frequencies that would not befit a deleterious function when affected as well as a high recorded pLOF (https://gnomad.broadinstitute.org/gene/ENSG00000176715). As such, this disorder has been asserted to be a benign metabolic phenotype in the literature (PMIDs: 21841779, 30740739). Functional studies into the effects of these variants in vitro or to determine any residual enzyme activity have not yet been performed. The mechanism for disease is biallelic loss of function, with disruption of the encoded mitochondrial malonyl-CoA and methylmalonyl-CoA synthetase causing a backup in intramitochondrial fatty acid synthesis and resulting buildup of malonic and methylmalonic acid in urine and tissues. This gene-disease association is supported by functional studies performed on patient tissue, with MMA production significantly lowered in patient fibroblasts compared to controls and the expression of WT ACSF3 cDNA, but not GFP, rescuing the metabolic phenotype and returning the production levels to near the controls. A natural canine model exhibiting the deficency also exists with homozygous variants in this gene, although there are other unexplained severe neurological symptoms in the line as well. In summary, ACSF3 is definitively associated with autosomal recessive combined malonic and methylmalonic acidemia (CMAMMA). Although more functional data examining the residual activity of variants and more experimental data could be acquired, the evidence currently provided is sufficent and has been upheld over time.

Clinical Genomic Database (CGD)

Combined malonic and methylmalonic aciduriaAR

Manifestation: Biochemical; Neurologic

Intervention: Biochemical

Rationale: Although the optimal treatment (as well as the requirement thereof) is currently unclear, additional monitoring may be warranted to determine whether medical management would be beneficial

Refs: 9700595; 21785126; 21841779; 30740739

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ACSF3 variants in ClinVar

7 Conditions Cataloged

Combined malonic and methylmalonic acidemiaTotal: 882

Inborn genetic diseasesTotal: 120

not providedTotal: 101

not specifiedTotal: 86

Methylmalonic acidemiaTotal: 64

ACSF3-related disorderTotal: 42

Global developmental delayTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001243279.3. 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			18 clinvar	346 clinvar	3 clinvar	367
missense	1 clinvar	15 clinvar	262 clinvar	19 clinvar		297
nonsense	12 clinvar	52 clinvar	1 clinvar			65
start loss		3 clinvar				3
frameshift	17 clinvar	66 clinvar	1 clinvar			84
splice donor/acceptor (+/-2bp)	3 clinvar	31 clinvar				34
Total	33	167	282	365	3	850

Highest pathogenic variant AF is 0.0045165042

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 41 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001243279.3	RefSeq	NP_001230208.1	9	MANE Select
ENST00000614302.5	Ensembl	ENSP00000479130.1	9	MANE Select
NM_001127214.4	RefSeq	NP_001120686.1	9	Standard
NM_001284316.2	RefSeq	NP_001271245.1	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Valine, leucine and isoleucine degradation - Homo sapiens (human)
Metabolism of lipids
Fatty acyl-CoA biosynthesis
Metabolism
Fatty acid metabolism

Biological Process

fatty acid metabolic process
fatty acid biosynthetic process
long-chain fatty-acyl-CoA biosynthetic process
malonate catabolic process

Molecular Function

ATP binding
acid-thiol ligase activity
very long-chain fatty acid-CoA ligase activity
malonyl-CoA synthetase activity

Cellular Component

mitochondrion
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000317447
Coding exons: 9
Length: 67472
Individuals with no LoFs: 125624
Homozygous LoFs: 1
Heterozygous LoFs: 123
Defined: 125748
p: 0.000493

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-1.30	426	357	1.19	0.0000238	3652
Missense (PolyPhen)		153	128.82	1.1877		1337
Synonymous	-2.81	207	161	1.28	0.0000122	1207
Loss of Function	-1.62	34	25.2	1.35	0.00000134	264

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00060	0.00058	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.0013	0.0013	notable
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00039	0.00038	rare
South Asian	0.00091	0.00088	rare
Other	0.00065	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the initial reaction in intramitochondrial fatty acid synthesis, by activating malonate and methylmalonate, but not acetate, into their respective CoA thioester. May have some preference toward very-long-chain substrates. {ECO:0000269|PubMed:17762044, ECO:0000269|PubMed:21841779}.;
Disease: DISEASE: Combined malonic and methylmalonic aciduria (CMAMMA) [MIM:614265]: A metabolic disease characterized by malonic and methylmalonic aciduria, with urinary excretion of much larger amounts of methylmalonic acid than malonic acid, in the presence of normal malonyl-CoA decarboxylase activity. Clinical features include coma, ketoacidosis, hypoglycemia, failure to thrive, microcephaly, dystonia, axial hypotonia and/or developmental delay, and neurologic manifestations including seizures, psychiatric disease and/or cognitive decline. {ECO:0000269|PubMed:21841779}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.925
RVIS EVS: -0.88
RVIS percentile EVS: 10.54

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.300

Gene Damage Prediction

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