ABCD4

ATP binding cassette subfamily D member 4, the group of ATP binding cassette subfamily D

Basic information

Region (hg38): 14:74285269-74303055

Previous symbols: [ "PXMP1L" ]

Links

ENSG00000119688 ∙ NCBI:5826 ∙ OMIM:603214 ∙ HGNC:68 ∙ Uniprot:O14678 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• methylmalonic acidemia with homocystinuria, type cblJ (Strong), mode of inheritance: AR
• methylmalonic acidemia with homocystinuria, type cblJ (Strong), mode of inheritance: AR
• methylmalonic acidemia with homocystinuria, type cblJ (Supportive), mode of inheritance: AR
• methylmalonic acidemia with homocystinuria, type cblJ (Moderate), mode of inheritance: AR
• methylmalonic acidemia with homocystinuria, type cblJ (Moderate), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Methylmalonic aciduria and homocystinuria, cblJ type	AR	Allergy/Immunology/Infectious; Biochemical; Cardiovascular	Administration of hydroxocobalamin/methylcobalamin has been described as beneficial; Due to infectious risks, administration of G-CSF has been described, and early and aggressive treatment of infections may be benefiical; Surveillance for cardiovascular manifestations may allow early management	Allergy/Immunology/Infectious; Biochemical; Cardiovascular; Neurologic	22922874; 23141461

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ABCD4 gene.

• Methylmalonic acidemia with homocystinuria, type cblJ (10 variants)
• Cobalamin C disease (2 variants)
• not provided (2 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ABCD4 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			3	67	7	77
missense	1	1	122	16	4	144
nonsense	3	1				4
start loss			1			1
frameshift	7	2	1			10
inframe indel						0
splice donor/acceptor (+/-2bp)	1	3	3			7
splice region			8	15	5	28
non coding			2	69	71	142
Total	12	7	132	152	82

Highest pathogenic variant AF is 0.0000197

Variants in ABCD4

This is a list of pathogenic ClinVar variants found in the ABCD4 region.

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

Position	Type	Phenotype	Significance	ClinVar
14-74286199-A-C			Benign (Jul 31, 2018)
14-74286273-G-A			Benign (Feb 08, 2019)
14-74286341-T-C			Benign (Jul 26, 2019)
14-74286404-C-G			Benign (Feb 08, 2019)
14-74286409-C-T			Benign (May 06, 2019)
14-74286438-C-T			Benign (Feb 08, 2019)
14-74286456-G-A		not specified	Likely benign (Aug 11, 2016)
14-74286464-T-C		Methylmalonic acidemia with homocystinuria, type cblJ	Likely benign (Apr 28, 2021)
14-74286468-A-G		Inborn genetic diseases	Uncertain significance (Dec 11, 2023)
14-74286477-C-G		Methylmalonic acidemia with homocystinuria, type cblJ	Uncertain significance (Sep 13, 2022)
14-74286488-C-G		Methylmalonic acidemia with homocystinuria, type cblJ	Uncertain significance (Apr 01, 2020)
14-74286501-CCA-C		not specified	Uncertain significance (Mar 09, 2022)
14-74286508-G-A		Methylmalonic acidemia with homocystinuria, type cblJ	Uncertain significance (Oct 05, 2022)
14-74286526-G-C		Inborn genetic diseases	Uncertain significance (Jan 12, 2021)
14-74286533-C-T		not specified • Methylmalonic acidemia with homocystinuria, type cblJ	Likely benign (Jun 13, 2022)
14-74286541-C-T			Uncertain significance (Aug 01, 2021)
14-74286547-C-T		not specified • Methylmalonic acidemia with homocystinuria, type cblJ	Conflicting classifications of pathogenicity (Jan 17, 2022)
14-74286575-T-C		Methylmalonic acidemia with homocystinuria, type cblJ	Benign (Jul 14, 2021)
14-74286660-G-A			Benign (Jun 23, 2018)
14-74286694-C-T		Methylmalonic acidemia with homocystinuria, type cblJ	Likely benign (Nov 09, 2021)
14-74286696-G-A		not specified • Methylmalonic acidemia with homocystinuria, type cblJ • ABCD4-related disorder	Benign (Jan 18, 2024)
14-74286699-A-G		Methylmalonic acidemia with homocystinuria, type cblJ	Uncertain significance (Aug 13, 2021)
14-74286706-C-CAG		Methylmalonic acidemia with homocystinuria, type cblJ	Pathogenic (Oct 01, 2012)
14-74286710-G-C		Methylmalonic acidemia with homocystinuria, type cblJ	Uncertain significance (Jun 13, 2022)
14-74286713-C-G		Inborn genetic diseases	Uncertain significance (Jan 07, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ABCD4	protein_coding	protein_coding	ENST00000356924	19	17634

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.34e-12	0.921	125672	0	76	125748	0.000302

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.169	347	356	0.975	0.0000211	3926
Missense in Polyphen		99	111.19	0.89039		1225
Synonymous	-0.725	162	151	1.08	0.00000942	1200
Loss of Function	2.06	25	38.9	0.643	0.00000203	408

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000456	0.000456
Ashkenazi Jewish	0.00	0.00
East Asian	0.000544	0.000544
Finnish	0.000186	0.000185
European (Non-Finnish)	0.000381	0.000378
Middle Eastern	0.000544	0.000544
South Asian	0.000165	0.000163
Other	0.000816	0.000815

dbNSFP

Source: dbNSFP

• Function: FUNCTION: May be involved in intracellular processing of vitamin B12 (cobalamin). Could play a role in the lysosomal release of vitamin B12 into the cytoplasm. {ECO:0000269|PubMed:22922874}.
• Pathway: Peroxisome - Homo sapiens (human);ABC transporters - Homo sapiens (human);Cobalamin (Cbl, vitamin B12) transport and metabolism;Metabolism;Metabolism of water-soluble vitamins and cofactors;Metabolism of vitamins and cofactors (Consensus)

Recessive Scores

• pRec: 0.153

Intolerance Scores

• loftool: 0.152
• rvis_EVS: 0.8
• rvis_percentile_EVS: 87.72

Haploinsufficiency Scores

• pHI: 0.141
• hipred: N
• hipred_score: 0.289
• ghis: 0.489

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.413

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High

Mouse Genome Informatics

• Gene name: Abcd4
• Phenotype: integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Gene ontology

• Biological process: cobalamin metabolic process;transmembrane transport;cellular response to leukemia inhibitory factor
• Cellular component: lysosomal membrane;peroxisome;peroxisomal membrane;endoplasmic reticulum membrane;integral component of membrane;ATP-binding cassette (ABC) transporter complex
• Molecular function: ATP binding;ATPase activity, coupled to transmembrane movement of substances