TAP1

protein-coding

transporter 1, ATP binding cassette subfamily B member, the group of ATP binding cassette subfamily B

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 intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance. The protein encoded by this gene is involved in the pumping of degraded cytosolic peptides across the endoplasmic reticulum into the membrane-bound compartment where class I molecules assemble. Mutations in this gene may be associated with ankylosing spondylitis, insulin-dependent diabetes mellitus, and celiac disease. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2014]

Previous symbols:

ABCB2

MANE transcript

NM_000593.6

Inheritance

ClinVar variants

P:29U:198B:158

Top phenotype

MHC class I deficiency 1

gnomAD constraint

pLI —, LoF o/e 0.43

Max pathogenic AF

—

Genomic locus

chr6:32,845,209-32,853,816

External References & Databases

Ensembl (ENSG00000168394)

Transcript & Mutation Effects

hg38 • Region Span ~8.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

MHC class I deficiency 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0971006

Submitter: G2P

MHC class I deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011476

Submitter: ClinGen

TAP1 was first reported in relation to autosomal recessive MHC class I deficiency in 1996 (Chen et al., PMID: 8640228). This condition is characterized by chronic upper and lower respiratory bacterial infections, chronic sinusitis, and ulcerating granulomatous skin disease in some cases. Affected individuals typically have normal immunoglobulins, low CD8+ alpha-beta T cells, and activation of natural killer and CD8+ gamma-delta T-cells. Seven variants (nonsense and frameshift) that have been reported in 7 probands in 6 publications (PMIDs: 30189467, 28161407, 18668571, 16624613, 16299152, 10074495) are included in this curation. Variants segregated with disease in three families (PMIDs: 16624613, 28161407, 16299152). Heterozygous parents were unaffected. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by mouse models, in vitro functional assays, and rescue in patient cells.) (PMIDs: 9952025, 10074495, 11118151). In summary, there is definitive evidence supporting the relationship between TAP1 and autosomal recessive MHC class I deficiency. 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 SCID-CID GCEP on the meeting date [July 20, 2023] (SOP Version [9]).

MHC class I deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011476

Submitter: Labcorp Genetics (formerly Invitae)

MHC class I deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011476

Submitter: Orphanet

MHC class I deficiency 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0971006

Submitter: PanelApp Australia

MHC class I deficiencyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0011476

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

MHC class I deficiency 1AR

Manifestation: Allergy/Immunology/Infectious; Pulmonary

Intervention: Allergy/Immunology/Infectious; Pulmonary

Rationale: Individuals may manifest with frequent and severe infections (including early-onset severe bacterial infections), and antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial; For pulmonary manifestations, treatment recommendations analogous to those in individuals cystic fibrosis have been recommended; Immunosuppressive therapy may be contraindicated

Comments: The condition has been reported as possibly related to increased risk of malignancy as well as infectious manifestations

Refs: 3891604; 10074495; 10074494; 10931128; 17498556; 17982230; 17315195; 18668571

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TAP1 variants in ClinVar

7 Conditions Cataloged

MHC class I deficiencyTotal: 386

Inborn genetic diseasesTotal: 83

not specifiedTotal: 22

not providedTotal: 17

TAP1-related disorderTotal: 9

MHC class I deficiency 1Total: 6

TAP1 deficiency, somaticTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000593.6. 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			3 clinvar	133 clinvar	4 clinvar	140
missense		1 clinvar	188 clinvar	21 clinvar		210
nonsense	15 clinvar	1 clinvar	2 clinvar			18
start loss						0
frameshift	9 clinvar	1 clinvar				10
splice donor/acceptor (+/-2bp)	1 clinvar	1 clinvar	5 clinvar			7
Total	25	4	198	154	4	385

Highest pathogenic variant AF is 0.00003346044

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 30 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000593.6	RefSeq	NP_000584.3	11	MANE Select
ENST00000354258.5	Ensembl	ENSP00000346206.5	11	MANE Select
NM_001292022.2	RefSeq	NP_001278951.1	10	Standard
ENST00000643049.2	Ensembl	ENSP00000494148.2	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Antigen processing and presentation - Homo sapiens (human)
Primary immunodeficiency - Homo sapiens (human)
Phagosome - Homo sapiens (human)
ABC transporters - Homo sapiens (human)
Herpes simplex infection - Homo sapiens (human)

Biological Process

adaptive immune response
antigen processing and presentation of peptide antigen via MHC class I
antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent
defense response
protein transport

Molecular Function

protein binding
ATP binding
peptide antigen-transporting ATPase activity
MHC class Ib protein binding
MHC class I protein binding

Cellular Component

endoplasmic reticulum
endoplasmic reticulum membrane
microtubule organizing center
membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000354258
Coding exons: 11
Length: 8770
Individuals with no LoFs: 125699
Homozygous LoFs: 0
Heterozygous LoFs: 49
Defined: 125748
p: 0.000195

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.77	327	430	0.760	0.0000239	5053
Missense (PolyPhen)		79	133.67	0.59101		1653
Synonymous	1.22	168	189	0.887	0.0000105	1794
Loss of Function	3.16	15	35.2	0.426	0.00000199	358

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00032	0.00031	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00038	0.00038	rare
Finnish	0.00024	0.00023	rare
European (Non-Finnish)	0.00023	0.00023	rare
South Asian	0.000065	0.000065	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the transport of antigens from the cytoplasm to the endoplasmic reticulum for association with MHC class I molecules. Also acts as a molecular scaffold for the final stage of MHC class I folding, namely the binding of peptide. Nascent MHC class I molecules associate with TAP via tapasin. Inhibited by the covalent attachment of herpes simplex virus ICP47 protein, which blocks the peptide-binding site of TAP. Inhibited by human cytomegalovirus US6 glycoprotein, which binds to the lumenal side of the TAP complex and inhibits peptide translocation by specifically blocking ATP-binding to TAP1 and prevents the conformational rearrangement of TAP induced by peptide binding. Inhibited by human adenovirus E3-19K glycoprotein, which binds the TAP complex and acts as a tapasin inhibitor, preventing MHC class I/TAP association. Expression of TAP1 is down-regulated by human Epstein-Barr virus vIL-10 protein, thereby affecting the transport of peptides into the endoplasmic reticulum and subsequent peptide loading by MHC class I molecules.;
Disease: DISEASE: Bare lymphocyte syndrome 1 (BLS1) [MIM:604571]: A HLA class I deficiency. Contrary to bare lymphocyte syndromes type 2 and type 3, which are characterized by early-onset severe combined immunodeficiency, class I antigen deficiencies are not accompanied by particular pathologic manifestations during the first years of life. Systemic infections have not been described. Chronic bacterial infections, often beginning in the first decade of life, are restricted to the respiratory tract. {ECO:0000269|PubMed:10074494}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.0865
RVIS EVS: 2.13
RVIS percentile EVS: 97.95

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.953

Gene Damage Prediction

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