ABCA3

protein-coding

ATP binding cassette subfamily A member 3, the group of ATP binding cassette subfamily A

Gene summary

The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intracellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the ABC1 subfamily. Members of the ABC1 subfamily comprise the only major ABC subfamily found exclusively in multicellular eukaryotes. The full transporter encoded by this gene may be involved in development of resistance to xenobiotics and engulfment during programmed cell death. [provided by RefSeq, Jul 2008]

Previous symbols:

ABC3

MANE transcript

NM_001089.3

Inheritance

ClinVar variants

P:206U:540B:708

Top phenotype

Surfactant metabolism dysfunction, pulmonary, 3

gnomAD constraint

pLI —, LoF o/e 0.36

Max pathogenic AF

—

Genomic locus

chr16:2,275,881-2,340,746

External References & Databases

Ensembl (ENSG00000167972)

Transcript & Mutation Effects

hg38 • Region Span ~64.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

interstitial lung disease due to ABCA3 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012582

Submitter: Genomics England PanelApp

interstitial lung disease due to ABCA3 deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012582

Submitter: Orphanet

interstitial lung disease due to ABCA3 deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012582

Submitter: ClinGen

*ABCA3* was first reported in relation to autosomal recessive interstitial lung disease due to *ABCA3* dysfunction in 2004 (Shulenin et al., PMID: 15044640). *ABCA3* encodes the ATP-binding cassette protein A3 which is primarily expressed in the alveolar type 2 cells of the lung and functions as a phospholipid transporter to move phospholipids into the lamellar body. Individuals with variants in *ABCA3* are often reported to have surfactant deficiency, respiratory distress, and failure in the neonatal period or in infancy, but variants have also been found in older children and adults with isolated chronic interstitial lung disease (PMID: 19220077). Of note, *ABCA3* has also been seen in monoallelic cases of ILD where another variant was also present (SFTPC p.I73T), but *ABCA3* was described as a modifier gene in those cases and they were not included in this curation (PMIDs: 17597647, 20371530). Fourteen variants (10 missense, 2 nonsense, 1 frameshift, 1 canonical splice site) that have been reported in 10 probands in 2 publications (PMIDs: 15044640, 32238781) are included in this curation. c.875A>T (p.Glu292Val) has been identified as a common variant seen in numerous patients with varying phenotypes (PMID: 32238781). More evidence is available in the literature, but the maximum score for genetic evidence has been reached. The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by the biochemical function being shared with other known genes (SFTPB and SFTPC) in the disease of interest (PMID: 19220077), expression data showing high expression in lung tissue (PMID: 23715323), functional alteration assays modeling the disrupted intracellular trafficking and impaired ATPase-mediated phospholipid transport into the lamellar bodies of *ABCA3* variants in A549 cells (PMID: 32196812) mouse models that exhibit respiratory failure, neonatal death, and abnormal lamellar bodies similar to the human phenotype (PMIDs: 17142808, 17577581, 17267394), and cell culture models displaying abnormal-appearing lamellar body–like vesicles with significantly smaller vesicle diameters (P < 0.001) compared to WT (PMID: 32692933). In summary, there is definitive evidence supporting the relationship between *ABCA3* and autosomal recessive interstitial lung disease due to *ABCA3* dysfunction. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Interstitial Lung Disease GCEP on September 17, 2024 (SOP Version 10).

interstitial lung disease due to ABCA3 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012582

Submitter: PanelApp Australia

interstitial lung disease due to ABCA3 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012582

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Surfactant metabolism dysfunction, pulmonary, 3AR

Manifestation: Pulmonary

Intervention: Pulmonary

Rationale: Individuals may present in infancy with severe respiratory insufficiency (a presentation in early childhood ascribed to a heterozygous variant has also beeen described), and diagnosis has important therapeutic implications, as BMT can be effective; Lung transplant may be beneficial in some individuals

Refs: 15044640; 15976379; 15819986; 15985750; 17719949; 22337229; 22304854; 23166334

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ABCA3 variants in ClinVar

18 Conditions Cataloged

not providedTotal: 1393

Hereditary pulmonary alveolar proteinosisTotal: 592

Interstitial lung disease due to ABCA3 deficiencyTotal: 369

not specifiedTotal: 140

ABCA3-related disorderTotal: 68

Interstitial lung disease 2Total: 15

Primary interstitial lung disease specific to childhood due to pulmonary surfactant protein anomaliesTotal: 4

Surfactant metabolism dysfunction, pulmonary, 1Total: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001089.3. 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		2 clinvar	6 clinvar	644 clinvar	1 clinvar	653
missense	5 clinvar	49 clinvar	522 clinvar	61 clinvar	2 clinvar	639
nonsense	54 clinvar	7 clinvar	4 clinvar			65
start loss		1 clinvar				1
frameshift	52 clinvar	17 clinvar	1 clinvar			70
splice donor/acceptor (+/-2bp)	4 clinvar	15 clinvar	7 clinvar			26
Total	115	91	540	705	3	1454

Highest pathogenic variant AF is 0.004533023

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 24 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001089.3	RefSeq	NP_001080.2	30	MANE Select
ENST00000301732.10	Ensembl	ENSP00000301732.5	30	MANE Select
ENST00000382381.7	Ensembl	ENSP00000371818.3	29	Standard
ENST00000382381.8	Ensembl	ENSP00000371818.3	29	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

ABC transporters - Homo sapiens (human)
ABC transporters in lipid homeostasis
Surfactant metabolism
Metabolism of proteins
Transport of small molecules

Biological Process

lipid transport
response to drug
cellular protein metabolic process
response to glucocorticoid
transmembrane transport

Molecular Function

transporter activity
lipid transporter activity
ATP binding
ATPase activity, coupled to transmembrane movement of substances

Cellular Component

extracellular space
plasma membrane
membrane
integral component of membrane
intracellular membrane-bounded organelle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000301732
Coding exons: 30
Length: 64866
Individuals with no LoFs: 125698
Homozygous LoFs: 0
Heterozygous LoFs: 50
Defined: 125748
p: 0.000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.323	995	1.02e+3	0.972	0.0000732	11067
Missense (PolyPhen)		203	259.83	0.78129		3007
Synonymous	-2.75	542	466	1.16	0.0000380	3484
Loss of Function	5.02	26	72.0	0.361	0.00000356	812

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00043	0.00043	rare
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.00016	0.00016	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00018	0.00018	rare
South Asian	0.00013	0.00013	rare
Other	0.00065	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays an important role in the formation of pulmonary surfactant, probably by transporting lipids such as cholesterol.;
Disease: DISEASE: Pulmonary surfactant metabolism dysfunction 3 (SMDP3) [MIM:610921]: A rare lung disorder due to impaired surfactant homeostasis. It is characterized by alveolar filling with floccular material that stains positive using the periodic acid- Schiff method and is derived from surfactant phospholipids and protein components. Excessive lipoproteins accumulation in the alveoli results in severe respiratory distress. {ECO:0000269|PubMed:15044640}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.170

Intolerance Scores

LoFtool: 0.0274
RVIS EVS: -1.48
RVIS percentile EVS: 3.71

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.737

Gene Damage Prediction

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