AP1S3

protein-coding

adaptor related protein complex 1 subunit sigma 3, the group of Adaptor related protein complex 1

Gene summary

This gene encodes a member of the adaptor-related protein complex 1, sigma subunit genes. The encoded protein is a component of adaptor protein complex 1 (AP-1), one of the AP complexes involved in claathrin-mediated vesicular transport from the Golgi or endosomes. Disruption of the pathway for display of HIV-1 antigens, which prevents recognition of the virus by cytotoxic T cells, has been shown to involve the AP-1 complex (PMID: 15569716). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

MANE transcript

NM_001039569.2

Inheritance

AD, AR

ClinVar variants

U:16B:11

Top phenotype

Psoriasis 15, pustular, susceptibility to

gnomAD constraint

pLI —, LoF o/e 0.47

Max pathogenic AF

—

Genomic locus

chr2:223,667,680-223,838,027

External References & Databases

Ensembl (ENSG00000152056)

Transcript & Mutation Effects

hg38 • Region Span ~170.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

psoriasis 15, pustular, susceptibility toMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0014494

Submitter: PanelApp Australia

psoriasis 14, pustularSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013626

Submitter: Orphanet

palmoplantar pustulosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015597

Submitter: Orphanet

psoriasis 15, pustular, susceptibility toSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014494

Submitter: G2P

psoriasis 14, pustularSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013626

Submitter: Orphanet

Clinical Genomic Database (CGD)

Psoriasis 15, pustular, susceptibility toAD

Manifestation: Allergy/Immunology/Infectious; Dermatologic

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: 24791904

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to AP1S3 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 27

AP1S3-related disorderTotal: 11

not providedTotal: 10

Psoriasis 15, pustular, susceptibility toTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001039569.2. 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		3
missense			14 clinvar	8 clinvar		22
nonsense			1 clinvar			1
start loss			1 clinvar			1
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	16	11	0	27

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 29 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001039569.2	RefSeq	NP_001034658.1	5	MANE Select
ENST00000396654.7	Ensembl	ENSP00000379891.2	5	MANE Select
ENST00000334271.7	Ensembl	ENSP00000333888.3	3	Standard
ENST00000396653.2	Ensembl	ENSP00000379890.2	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Lysosome - Homo sapiens (human)
Golgi Associated Vesicle Biogenesis
Lysosome Vesicle Biogenesis
Clathrin derived vesicle budding
Disease

Biological Process

protein targeting
vesicle-mediated transport
antigen processing and presentation of exogenous peptide antigen via MHC class II
regulation of defense response to virus by virus

Molecular Function

protein binding

Cellular Component

Golgi membrane
lysosomal membrane
cytosol
clathrin-coated pit
membrane coat

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000396654
Coding exons: 5
Length: 86342
Individuals with no LoFs: 124762
Homozygous LoFs: 0
Heterozygous LoFs: 14
Defined: 124776
p: 0.0000561

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.507	70	83.0	0.843	0.00000446	1021
Missense (PolyPhen)		35	39.853	0.87823		453
Synonymous	1.31	19	27.8	0.685	0.00000138	260
Loss of Function	1.43	4	8.48	0.472	4.20e-7	110

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000065	0.000065	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000044	0.000044	rare
South Asian	0.000098	0.000098	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Subunit of clathrin-associated adaptor protein complex 1 that plays a role in protein sorting in the late-Golgi/trans-Golgi network (TGN) and/or endosomes. The AP complexes mediate both the recruitment of clathrin to membranes and the recognition of sorting signals within the cytosolic tails of transmembrane cargo molecules. Involved in TLR3 trafficking (PubMed:24791904). {ECO:0000269|PubMed:24791904}.;

Recessive Scores

pRec: 0.103

Intolerance Scores

LoFtool: 0.438
RVIS EVS: 1.3
RVIS percentile EVS: 93.94

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.533

Gene Damage Prediction

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