AP4B1

protein-coding

adaptor related protein complex 4 subunit beta 1, the group of Clathrin/coatomer adaptor, adaptin-like, N-terminal domain containing|Adaptor related protein complex 4

Gene summary

This gene encodes a subunit of a heterotetrameric adapter-like complex 4 that is involved in targeting proteins from the trans-Golgi network to the endosomal-lysosomal system. Mutations in this gene are associated with cerebral palsy spastic quadriplegic type 5 (CPSQ5) disorder. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

Previous symbols:

SPG47

MANE transcript

NM_001253852.3

Inheritance

ClinVar variants

P:74U:249B:109

Top phenotype

Spastic paraplegia 47, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.57

Max pathogenic AF

—

Genomic locus

chr1:113,894,194-113,905,712

External References & Databases

Ensembl (ENSG00000134262)

Transcript & Mutation Effects

hg38 • Region Span ~11.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

AP-4 deficiency syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100176

Submitter: ClinGen

*AP4B1* loss-of-function variants were first reported in relation to autosomal recessive Adaptor Protein 4 (AP4) deficiency syndrome in 2011 (PMID: 21620353). AP4 deficiency results in severe early-onset developmental delay with motor and speech delay, intellectual disability, hypotonia in infancy followed by spastic paraplegia and later tetraplegia, microcephaly, and seizures (PMID: 32979048). At least 53 individuals from 40 families with biallelic *AP4B1* nonsense, frameshift, splicing and missense variants leading to loss of protein function have been reported (PMIDs: 21620353, 24781758, 29193663, 32979048). This gene-disease relationship is also supported by biochemical and functional evidence demonstrating loss of AP4 complex function and impaired protein localization in fibroblasts from patients with biallelic *AP4B1* loss-of-function variants, with the impaired protein localization rescued upon re-expression of AP4B1 (PMID: 31915823). In summary, there is definitive evidence supporting the relationship between *AP4B1* and autosomal recessive AP4 deficiency syndrome. 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 Intellectual Disability and Autism Gene Curation Expert Panel on July 26, 2021 (SOP Version 8).

hereditary spastic paraplegia 47STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013551

Submitter: PanelApp Australia

AP4-related intellectual disability and spastic paraplegiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017241

Submitter: Orphanet

hereditary spastic paraplegia 47STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013551

Submitter: G2P

hereditary spastic paraplegia 47MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013551

Submitter: Ambry Genetics

hereditary spastic paraplegia 47STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013551

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Spastic paraplegia 47, autosomal recessiveAR

Manifestation: Craniofacial; Musculoskeletal; Neurologic

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: 21620353; 22290197; 24700674; 24781758

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to AP4B1 variants in ClinVar

12 Conditions Cataloged

Hereditary spastic paraplegia 47Total: 328

Inborn genetic diseasesTotal: 171

not providedTotal: 105

not specifiedTotal: 48

Spastic paraplegiaTotal: 30

Hereditary spastic paraplegiaTotal: 23

AP4B1-related disorderTotal: 15

Intellectual disabilityTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001253852.3. 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			5 clinvar	92 clinvar	1 clinvar	98
missense		7 clinvar	240 clinvar	15 clinvar	1 clinvar	263
nonsense	13 clinvar	11 clinvar				24
start loss	1 clinvar	1 clinvar	2 clinvar			4
frameshift	21 clinvar	13 clinvar	1 clinvar			35
splice donor/acceptor (+/-2bp)	3 clinvar	4 clinvar	1 clinvar			8
Total	38	36	249	107	2	432

Highest pathogenic variant AF is 0.00012391405

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 118 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001253852.3	RefSeq	NP_001240781.1	10	MANE Select
ENST00000369569.6	Ensembl	ENSP00000358582.1	10	MANE Select
NM_001253853.3	RefSeq	NP_001240782.1	9	Standard
NM_001308312.2	RefSeq	NP_001295241.1	7	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
trans-Golgi Network Vesicle Budding

Biological Process

protein targeting
protein localization
vesicle-mediated transport

Molecular Function

protein binding
clathrin binding

Cellular Component

trans-Golgi network
cytosol
extrinsic component of membrane
AP-4 adaptor complex
clathrin adaptor complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000369569
Coding exons: 10
Length: 10454
Individuals with no LoFs: 125609
Homozygous LoFs: 0
Heterozygous LoFs: 139
Defined: 125748
p: 0.000553

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.131	398	405	0.982	0.0000227	4813
Missense (PolyPhen)		127	136.44	0.93078		1680
Synonymous	-0.0565	152	151	1.01	0.00000796	1469
Loss of Function	2.37	20	35.1	0.569	0.00000206	389

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00049	0.00049	rare
Latino/Admixed American	0.00052	0.00052	rare
Ashkenazi Jewish	0.00099	0.00099	rare
East Asian	0.00022	0.00022	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00066	0.00066	rare
South Asian	0.00065	0.00065	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the adaptor protein complex 4 (AP-4). Adaptor protein complexes are vesicle coat components involved both in vesicle formation and cargo selection. They control the vesicular transport of proteins in different trafficking pathways (PubMed:10066790, PubMed:10436028). AP-4 forms a non clathrin- associated coat on vesicles departing the trans-Golgi network (TGN) and may be involved in the targeting of proteins from the trans-Golgi network (TGN) to the endosomal-lysosomal system. It is also involved in protein sorting to the basolateral membrane in epithelial cells and the proper asymmetric localization of somatodendritic proteins in neurons. AP-4 is involved in the recognition and binding of tyrosine-based sorting signals found in the cytoplasmic part of cargos, but may also recognize other types of sorting signal (Probable). {ECO:0000269|PubMed:10066790, ECO:0000269|PubMed:10436028, ECO:0000305|PubMed:10066790, ECO:0000305|PubMed:10436028}.;

Recessive Scores

pRec: 0.111

Intolerance Scores

LoFtool: 0.939
RVIS EVS: -0.13
RVIS percentile EVS: 44.03

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.975

Gene Damage Prediction

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