AP4M1

protein-coding

adaptor related protein complex 4 subunit mu 1, the group of Adaptor related protein complex 4

Gene summary

This gene encodes a subunit of the heterotetrameric AP-4 complex. The encoded protein belongs to the adaptor complexes medium subunits family. This AP-4 complex is involved in the recognition and sorting of cargo proteins with tyrosine-based motifs from the trans-golgi network to the endosomal-lysosomal system. [provided by RefSeq, Jul 2008]

MANE transcript

NM_004722.4

Inheritance

ClinVar variants

P:72U:184B:110

Top phenotype

Spastic paraplegia 50, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.95

Max pathogenic AF

—

Genomic locus

chr7:100,100,858-100,110,345

External References & Databases

Ensembl (ENSG00000221838)

Transcript & Mutation Effects

hg38 • Region Span ~9.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hereditary spastic paraplegia 50DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013048

Submitter: Ambry Genetics

hereditary spastic paraplegia 50STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013048

Submitter: Labcorp Genetics (formerly Invitae)

AP-4 deficiency syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100176

Submitter: ClinGen

*AP4M1* loss-of-function variants were first reported in relation to autosomal recessive Adaptor Protein 4 (AP4) deficiency syndrome in 2009 (PMID: 19559397). 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 59 individuals from 34 families with biallelic *AP4M1* nonsense, frameshift, splicing and large deletion variants leading to loss of protein function have been reported (PMIDs: 19559397, 24700674, 25496299, 29096665, 32979048). This gene-disease relationship is also supported by biochemical and functional evidence demonstrating loss of AP4 complex function and abnormal glutamate receptor GluRδ2 staining in dendrites of post-mortem brain samples from patients with *AP4M1* loss-of-function variants (PMID: 19559397). In summary, there is definitive evidence supporting the relationship between *AP4M1* 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 April 7, 2021 (SOP Version 8).

hereditary spastic paraplegia 50STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013048

Submitter: PanelApp Australia

hereditary spastic paraplegia 50STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013048

Submitter: G2P

AP4-related intellectual disability and spastic paraplegiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017241

Submitter: Orphanet

hereditary spastic paraplegia 50MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013048

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Spastic paraplegia 50, autosomal recessiveAR

Manifestation: 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: 19559397; 21937992

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to AP4M1 variants in ClinVar

15 Conditions Cataloged

Hereditary spastic paraplegia 50Total: 349

not providedTotal: 119

Inborn genetic diseasesTotal: 85

not specifiedTotal: 58

AP4M1-related disorderTotal: 35

Spastic paraplegiaTotal: 25

Hereditary spastic paraplegiaTotal: 22

Intellectual disabilityTotal: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004722.4. 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	102 clinvar		107
missense	1 clinvar	7 clinvar	173 clinvar	7 clinvar	1 clinvar	189
nonsense	10 clinvar	6 clinvar				16
start loss			1 clinvar			1
frameshift	15 clinvar	18 clinvar				33
splice donor/acceptor (+/-2bp)	3 clinvar	12 clinvar	5 clinvar			20
Total	29	43	184	109	1	366

Highest pathogenic variant AF is 0.000032838892

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 79 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004722.4	RefSeq	NP_004713.2	15	MANE Select
ENST00000359593.9	Ensembl	ENSP00000352603.4	15	MANE Select
NM_001363671.2	RefSeq	NP_001350600.1	15	Standard
NM_001438824.1	RefSeq	NP_001425753.1	15	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Lysosome - Homo sapiens (human)
Lysosome Vesicle Biogenesis
Clathrin derived vesicle budding
trans-Golgi Network Vesicle Budding
Vesicle-mediated transport

Biological Process

protein targeting
protein targeting to lysosome
intracellular protein transport
Golgi to endosome transport
protein localization

Molecular Function

protein binding
protein domain specific binding

Cellular Component

early endosome
trans-Golgi network
cytosol
AP-4 adaptor complex
clathrin adaptor complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000359593
Coding exons: 15
Length: 8797
Individuals with no LoFs: 125633
Homozygous LoFs: 0
Heterozygous LoFs: 115
Defined: 125748
p: 0.000457

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-1.21	311	256	1.21	0.0000169	2910
Missense (PolyPhen)		100	84.422	1.1845		968
Synonymous	-3.23	151	108	1.39	0.00000723	960
Loss of Function	0.259	26	27.5	0.947	0.00000162	292

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00062	0.00062	rare
Latino/Admixed American	0.00026	0.00026	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00044	0.00044	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00058	0.00058	rare
South Asian	0.00059	0.00059	rare
Other	0.00049	0.00049	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:10436028, PubMed:11139587, PubMed:10066790, PubMed:11802162, PubMed:20230749). 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 (PubMed:11139587, PubMed:20230749). It is also involved in protein sorting to the basolateral membrane in epithelial cells and the proper asymmetric localization of somatodendritic proteins in neurons (By similarity). Within AP-4, the mu-type subunit AP4M1 is directly involved in the recognition and binding of tyrosine-based sorting signals found in the cytoplasmic part of cargos (PubMed:10436028, PubMed:11139587, PubMed:26544806, PubMed:20230749). The adaptor protein complex 4 (AP-4) may also recognize other types of sorting signal (By similarity). {ECO:0000250|UniProtKB:E2RED8, ECO:0000250|UniProtKB:Q2PWT8, ECO:0000250|UniProtKB:Q9JKC7, ECO:0000269|PubMed:10066790, ECO:0000269|PubMed:10436028, ECO:0000269|PubMed:11139587, ECO:0000269|PubMed:11802162, ECO:0000269|PubMed:20230749, ECO:0000269|PubMed:26544806}.;

Recessive Scores

pRec: 0.138

Intolerance Scores

LoFtool: 0.788
RVIS EVS: -1.18
RVIS percentile EVS: 5.97

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.973

Gene Damage Prediction

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