ACBD5

protein-coding

acyl-CoA binding domain containing 5

Gene summary

This gene encodes a member of the acyl-Coenzyme A binding protein family, known to function in the transport and distribution of long chain acyl-Coenzyme A in cells. This gene may play a role in the differentiation of megakaryocytes and formation of platelets. A related protein in yeast is involved in autophagy of peroxisomes. A mutation in this gene has been associated with autosomal dominant thrombocytopenia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

MANE transcript

NM_145698.5

Inheritance

ClinVar variants

P:27U:173B:98

Top phenotype

Retinal dystrophy with leukodystrophy

gnomAD constraint

pLI —, LoF o/e 0.31

Max pathogenic AF

—

Genomic locus

chr10:27,168,135-27,243,046

External References & Databases

Ensembl (ENSG00000107897)

Transcript & Mutation Effects

hg38 • Region Span ~74.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

retinal dystrophy with leukodystrophyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0030026

Submitter: Ambry Genetics

retinal dystrophy with leukodystrophySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030026

Submitter: Labcorp Genetics (formerly Invitae)

retinal dystrophy with leukodystrophySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030026

Submitter: G2P

acyl-CoA binding domain containing protein 5 deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100112

Submitter: ClinGen

*ACBD5* was first reported in relation to autosomal recessive ACBD5 deficiency in 2013 (Abu-Safieh L et al., PMID: 23105016). More than ten pathogenic/likely pathogenic variants have been reported in humans per ClinVar. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of case-level (12 pts) and experimental data (3.5 pts): 15.5 points. Variants in this gene have been reported in at least 5 probands in 5 publications (PMID: 23105016, PMID: 27799409, PMID:33427402, PMID: 37789430, PMID: 34668366). The mechanism for disease is expected to be loss of function. This gene-disease association is supported by in vitro functional assays. At the time of curation (April 2020), this gene did not have associated disease entities per OMIM, but subsequently "Retinal dystrophy with leukodystrophy" was added as the disease entity. There have been associations with retinal dystrophy (PMID:23105016) and ACBD5 deficiency (PMID:27799409) in the literature. Additionally, there has been a report of an association with autosomal dominant thrombocytopenia (PMID:20626622), but this was later disputed (PMID:21211618). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability among the reports of retinal dystrophy and ACBD5 deficiency. Therefore, all of the disease entities have been lumped into one disease entity, ACBD5 deficiency (MONDO:0100112). In summary, *ACBD5* is definitively associated with ACBD5 deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the Peroxisomal Disorders GCEP on April 20, 2022 as a moderate classification. It was reevaluated on May 2, 2024. As a result of this reevaluation, the classification was upgraded from Moderate to Definitive.

retinal dystrophy with leukodystrophySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030026

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Retinal dystrophy with leukodystrophyAR

Manifestation: Biochemical; Craniofacial; Neurologic; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 23105016; 27799409

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ACBD5 variants in ClinVar

9 Conditions Cataloged

not providedTotal: 344

Inborn genetic diseasesTotal: 56

ACBD5-related disorderTotal: 26

Retinal dystrophy with leukodystrophyTotal: 10

Cone-rod dystrophyTotal: 2

Retinal dystrophyTotal: 2

not specifiedTotal: 2

Retinal disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_145698.5. 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			4 clinvar	82 clinvar	3 clinvar	89
missense			163 clinvar	9 clinvar	4 clinvar	176
nonsense	7 clinvar	4 clinvar	1 clinvar			12
start loss						0
frameshift	5 clinvar	2 clinvar	1 clinvar			8
splice donor/acceptor (+/-2bp)	1 clinvar	8 clinvar	4 clinvar			13
Total	13	14	173	91	7	298

Highest pathogenic variant AF is 0.000119584765

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 86 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_145698.5	RefSeq	NP_663736.2	13	MANE Select
ENST00000396271.8	Ensembl	ENSP00000379568.3	13	MANE Select
NM_001042473.4	RefSeq	NP_001035938.1	12	Standard
NM_001271512.3	RefSeq	NP_001258441.1	12	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Metabolism of lipids
Peroxisomal lipid metabolism
Metabolism
Fatty acid metabolism

Biological Process

fatty acid catabolic process
macroautophagy
autophagy of peroxisome
aggrephagy

Molecular Function

fatty-acyl-CoA binding
molecular_function
lipid binding

Cellular Component

nucleus
nucleoplasm
peroxisome
peroxisomal membrane
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000396271
Coding exons: 13
Length: 46914
Individuals with no LoFs: 125712
Homozygous LoFs: 0
Heterozygous LoFs: 36
Defined: 125748
p: 0.000143

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.873	246	288	0.855	0.0000146	3491
Missense (PolyPhen)		67	95.78	0.69952		1191
Synonymous	-0.464	108	102	1.06	0.00000570	937
Loss of Function	3.61	10	32.0	0.312	0.00000154	367

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00020	0.00020	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00021	0.00021	rare
South Asian	0.000098	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Acyl-CoA binding protein which acts as the peroxisome receptor for pexophagy but is dispensable for aggrephagy and nonselective autophagy. Binds medium- and long-chain acyl-CoA esters. {ECO:0000269|PubMed:24535825}.;

Recessive Scores

pRec: 0.0700

Intolerance Scores

LoFtool: 0.302
RVIS EVS: -0.56
RVIS percentile EVS: 19.73

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.418

Gene Damage Prediction

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