ABCA4

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

Basic information

Region (hg38): 1:93992834-94121148

Previous symbols: [ "STGD1", "ABCR", "RP19", "STGD" ]

Links

ENSG00000198691 ∙ NCBI:24 ∙ OMIM:601691 ∙ HGNC:34 ∙ Uniprot:P78363 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• severe early-childhood-onset retinal dystrophy (Definitive), mode of inheritance: AR
• cone-rod dystrophy 3 (Definitive), mode of inheritance: AR
• severe early-childhood-onset retinal dystrophy (Definitive), mode of inheritance: AR
• Stargardt disease (Supportive), mode of inheritance: AD
• retinitis pigmentosa (Supportive), mode of inheritance: AD
• cone-rod dystrophy (Supportive), mode of inheritance: AD
• cone-rod dystrophy 3 (Strong), mode of inheritance: AR
• retinitis pigmentosa 19 (Strong), mode of inheritance: AR
• severe early-childhood-onset retinal dystrophy (Strong), mode of inheritance: AR
• ABCA4-related retinopathy (Definitive), mode of inheritance: AR
• cone-rod dystrophy 3 (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Cone-rod dystrophy 3; Retinitis pigmentosa 19; Stargardt disease 1; Retinal dystrophy, early-onset severe; Fundus flavimaculatus; Macular degeneration, age-related, 2	AD/AR	General	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	Ophthalmologic	9054934; 9466990; 9425888; 9781034; 10396622; 10442900; 10874631; 10396622; 11818392; 12515255; 12796258; 16896346; 16682602; 11385708; 21510770; 21786275; 22229821; 22312191; 22328824; 22395892; 22661473; 22863181; 23096905

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ABCA4 gene.

• not_provided (3669 variants)
• Retinal_dystrophy (834 variants)
• Severe_early-childhood-onset_retinal_dystrophy (540 variants)
• ABCA4-related_disorder (271 variants)
• Cone-rod_dystrophy_3 (237 variants)
• Retinitis_pigmentosa_19 (230 variants)
• Age_related_macular_degeneration_2 (211 variants)
• Stargardt_disease (173 variants)
• Inborn_genetic_diseases (172 variants)
• not_specified (149 variants)
• Retinitis_pigmentosa (96 variants)
• Macular_degeneration (73 variants)
• Retinitis_Pigmentosa,_Recessive (71 variants)
• Cone-Rod_Dystrophy,_Recessive (70 variants)
• Stargardt_Disease,_Recessive (69 variants)
• Cone-rod_dystrophy (34 variants)
• Stargardt_disease_3 (29 variants)
• Macular_dystrophy (22 variants)
• ABCA4-related_retinopathy (21 variants)
• Cone_dystrophy (11 variants)
• Optic_atrophy (11 variants)
• Autosomal_recessive_retinitis_pigmentosa (11 variants)
• Isolated_macular_dystrophy (8 variants)
• Retinal_disorders (7 variants)
• See_cases (5 variants)
• Visual_impairment (5 variants)
• maculopathy (5 variants)
• MACULAR_DEGENERATION,_AGE-RELATED,_2,_SUSCEPTIBILITY_TO (3 variants)
• Generalized_choriocapillaris_dystrophy (3 variants)
• Abnormality_of_the_eye (3 variants)
• Peripheral_neuropathy (2 variants)
• Central_scotoma (2 variants)
• Cone_dystrophy_and_rod_monochromatism (2 variants)
• Retinitis_pigmentosa_1 (2 variants)
• Retinal_atrophy (2 variants)
• Retinal_dystrophy,_early-onset_severe (2 variants)
• Progressive_cone_dystrophy_(without_rod_involvement) (2 variants)
• Abnormal_retinal_morphology (2 variants)
• Bietti_crystalline_corneoretinal_dystrophy (2 variants)
• Congenital_stationary_night_blindness (2 variants)
• Retinal_disorder (2 variants)
• Vitreoretinopathy (2 variants)
• Benign_concentric_annular_macular_dystrophy (2 variants)
• Age-related_macular_degeneration (2 variants)
• Leber_congenital_amaurosis (2 variants)
• Late-onset_cone-rod_dystrophy (2 variants)
• Abnormal_macular_morphology (2 variants)
• Syndromic_retinitis_pigmentosa (1 variants)
• Visual_loss (1 variants)
• Mandibulofacial_dysostosis_with_mental_deficiency (1 variants)
• Leber_congenital_amaurosis_14 (1 variants)
• Blindness (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ABCA4 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000000350.3. Only rare variants are included in the table.

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.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous	2	5	45	716	16	784
missense	196	586	953	71	4	1810
nonsense	149	37	8			194
start loss	2	2				4
frameshift	252	61	32			345
splice donor/acceptor (+/-2bp)	106	82	16			204
Total	707	773	1054	787	20

Highest pathogenic variant AF is 0.007055086

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ABCA4	protein_coding	protein_coding	ENST00000370225	50	128296

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
5.35e-48	0.00607	125508	0	240	125748	0.000955

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.658	1306	1.24e+3	1.05	0.0000746	14895
Missense in Polyphen		430	459.99	0.93481		5686
Synonymous	-1.57	542	497	1.09	0.0000319	4485
Loss of Function	2.37	89	117	0.763	0.00000624	1336

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00144	0.00144
Ashkenazi Jewish	0.000300	0.000298
East Asian	0.000925	0.000925
Finnish	0.000231	0.000231
European (Non-Finnish)	0.00106	0.00106
Middle Eastern	0.000925	0.000925
South Asian	0.00187	0.00186
Other	0.000507	0.000489

dbNSFP

Source: dbNSFP

• Function: FUNCTION: In the visual cycle, acts as an inward-directed retinoid flipase, retinoid substrates imported by ABCA4 from the extracellular or intradiscal (rod) membrane surfaces to the cytoplasmic membrane surface are all-trans-retinaldehyde (ATR) and N-retinyl-phosphatidyl-ethanolamine (NR-PE). Once transported to the cytoplasmic surface, ATR is reduced to vitamin A by trans- retinol dehydrogenase (tRDH) and then transferred to the retinal pigment epithelium (RPE) where it is converted to 11-cis-retinal. May play a role in photoresponse, removing ATR/NR-PE from the extracellular photoreceptor surfaces during bleach recovery. {ECO:0000269|PubMed:10075733}.
• Disease: DISEASE: Fundus flavimaculatus (FFM) [MIM:248200]: Autosomal recessive retinal disorder very similar to Stargardt disease. In contrast to Stargardt disease, FFM is characterized by later onset and slowly progressive course. {ECO:0000269|PubMed:11379881, ECO:0000269|PubMed:11385708, ECO:0000269|PubMed:9781034}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Macular degeneration, age-related, 2 (ARMD2) [MIM:153800]: A form of age-related macular degeneration, a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane. {ECO:0000269|PubMed:19028736, ECO:0000269|PubMed:9295268}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Cone-rod dystrophy 3 (CORD3) [MIM:604116]: An inherited retinal dystrophy characterized by retinal pigment deposits visible on fundus examination, predominantly in the macular region, and initial loss of cone photoreceptors followed by rod degeneration. This leads to decreased visual acuity and sensitivity in the central visual field, followed by loss of peripheral vision. Severe loss of vision occurs earlier than in retinitis pigmentosa, due to cone photoreceptors degenerating at a higher rate than rod photoreceptors. {ECO:0000269|PubMed:10958761, ECO:0000269|PubMed:11385708, ECO:0000269|PubMed:11527935}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Retinitis pigmentosa 19 (RP19) [MIM:601718]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. RP19 is characterized by choroidal atrophy. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: ABC transporters - Homo sapiens (human);Signaling by GPCR;Signal Transduction;The canonical retinoid cycle in rods (twilight vision);Transport of small molecules;ABC-family proteins mediated transport;G alpha (i) signalling events;Visual phototransduction;GPCR downstream signalling (Consensus)

Recessive Scores

• pRec: 0.388

Intolerance Scores

• loftool: 0.0107
• rvis_EVS: 0.74
• rvis_percentile_EVS: 86.31

Haploinsufficiency Scores

• pHI: 0.0992
• hipred: N
• hipred_score: 0.448

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.704

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Abca4
• Phenotype: pigmentation phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; vision/eye phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); skeleton phenotype; homeostasis/metabolism phenotype; immune system phenotype

Gene ontology

• Biological process: retinoid metabolic process;phospholipid transfer to membrane;lipid transport;visual perception;phototransduction, visible light;phospholipid translocation;photoreceptor cell maintenance;transmembrane transport
• Cellular component: integral component of plasma membrane;membrane;intracellular membrane-bounded organelle;photoreceptor disc membrane
• Molecular function: phospholipid-translocating ATPase activity;transporter activity;lipid transporter activity;eye pigment precursor transporter activity;ATP binding;phospholipid transporter activity;ATPase activity;ATPase activity, coupled to transmembrane movement of substances;phosphatidylethanolamine-translocating ATPase activity