ACSF3

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

Basic information

Region (hg38): 16:89088375-89164121

Links

ENSG00000176715 ∙ NCBI:197322 ∙ OMIM:614245 ∙ HGNC:27288 ∙ Uniprot:Q4G176 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• combined malonic and methylmalonic acidemia (Strong), mode of inheritance: AR
• combined malonic and methylmalonic acidemia (Supportive), mode of inheritance: AD
• combined malonic and methylmalonic acidemia (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Combined malonic and methylmalonic aciduria	AR	Biochemical	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	Biochemical; Neurologic	9700595; 21785126; 21841779; 30740739

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ACSF3 gene.

• Combined malonic and methylmalonic acidemia (43 variants)
• Methylmalonic acidemia (2 variants)
• not provided (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ACSF3 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				315	13	328
missense		5	155	11	3	174
nonsense	19	38				57
start loss			1			1
frameshift	23	44	1			68
inframe indel						0
splice donor/acceptor (+/-2bp)	1	29				30
splice region			8	46	4	58
non coding			4	112	59	175
Total	43	116	161	438	75

Highest pathogenic variant AF is 0.0000263

Variants in ACSF3

This is a list of pathogenic ClinVar variants found in the ACSF3 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
16-89093708-C-T			Likely benign (Jun 24, 2021)
16-89093730-G-A			Likely benign (Feb 24, 2022)
16-89093750-G-C			Benign (Jun 29, 2018)
16-89093755-G-A			Benign (Jun 24, 2021)
16-89093807-C-A			Benign (Jun 24, 2021)
16-89093875-C-G			Benign (Mar 17, 2021)
16-89093921-C-G			Benign (Jun 23, 2018)
16-89094010-G-C		not specified	Likely benign (Feb 06, 2018)
16-89094016-C-G			Likely benign (Mar 29, 2018)
16-89094044-A-G			Benign (Jun 29, 2018)
16-89094053-G-A			Likely benign (Jun 24, 2021)
16-89094080-T-A			Likely benign (Nov 24, 2021)
16-89098566-C-A			Benign (Jun 23, 2018)
16-89098577-A-G		not specified	Benign (Jul 17, 2015)
16-89098586-G-C			Likely benign (Apr 13, 2018)
16-89098597-C-T			Likely benign (May 21, 2018)
16-89098748-C-T			Likely benign (May 03, 2018)
16-89098754-C-A		not specified	Likely benign (Jan 19, 2017)
16-89098754-C-G			Likely benign (May 04, 2018)
16-89098755-G-C		not specified	Likely benign (Sep 20, 2016)
16-89098761-T-C			Uncertain significance (Oct 17, 2017)
16-89098762-G-C		not specified	Likely benign (Feb 07, 2017)
16-89100399-A-G			Benign (Jul 07, 2018)
16-89100424-G-A			Benign (Jul 07, 2018)
16-89100533-C-T		Combined malonic and methylmalonic acidemia	Benign (Jul 14, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ACSF3	protein_coding	protein_coding	ENST00000317447	9	67472

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
2.32e-26	0.00000743	125624	1	123	125748	0.000493

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-1.30	426	357	1.19	0.0000238	3652
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000844	0.000843
Ashkenazi Jewish	0.0000993	0.0000992
East Asian	0.00127	0.00125
Finnish	0.0000928	0.0000924
European (Non-Finnish)	0.000385	0.000378
Middle Eastern	0.00127	0.00125
South Asian	0.000915	0.000882
Other	0.000653	0.000652

dbNSFP

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.
• Pathway: Valine, leucine and isoleucine degradation - Homo sapiens (human);Metabolism of lipids;Fatty acyl-CoA biosynthesis;Metabolism;Fatty acid metabolism;Synthesis of very long-chain fatty acyl-CoAs (Consensus)

Intolerance Scores

• loftool: 0.925
• rvis_EVS: -0.88
• rvis_percentile_EVS: 10.54

Haploinsufficiency Scores

• pHI: 0.105
• hipred: N
• hipred_score: 0.213
• ghis: 0.535

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.300

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Acsf3

Gene ontology

• Biological process: fatty acid metabolic process;fatty acid biosynthetic process;long-chain fatty-acyl-CoA biosynthetic process;malonate catabolic process
• Cellular component: mitochondrion;mitochondrial matrix
• Molecular function: ATP binding;acid-thiol ligase activity;very long-chain fatty acid-CoA ligase activity;malonyl-CoA synthetase activity