AP4M1

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

Basic information

Region (hg38): 7:100101548-100110345

Links

ENSG00000221838 ∙ NCBI:9179 ∙ OMIM:602296 ∙ HGNC:574 ∙ Uniprot:O00189 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hereditary spastic paraplegia 50 (Strong), mode of inheritance: AR
• hereditary spastic paraplegia 50 (Moderate), mode of inheritance: AR
• AP4-related intellectual disability and spastic paraplegia (Supportive), mode of inheritance: AR
• hereditary spastic paraplegia 50 (Strong), mode of inheritance: AR
• AP-4 deficiency syndrome (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Spastic paraplegia 50, autosomal recessive	AR	General	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	Neurologic	19559397; 21937992

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the AP4M1 gene.

• Hereditary spastic paraplegia 50 (288 variants)
• not provided (136 variants)
• not specified (34 variants)
• Inborn genetic diseases (33 variants)
• Hereditary spastic paraplegia (26 variants)
• Spastic paraplegia (18 variants)
• Alazami-Yuan syndrome (8 variants)
• Intellectual disability (6 variants)
• AP4M1-related condition (3 variants)
• AP-4 deficiency syndrome (2 variants)
• Hypoplasia of the corpus callosum;CNS hypomyelination;Brain atrophy;Global developmental delay;Microcephaly (1 variants)
• Abnormality of the nervous system (1 variants)
• Spastic tetraparesis (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the AP4M1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			7	62	3	72
missense	1	2	115	2	2	122
nonsense	10	2				12
start loss			1			1
frameshift	14	6				20
inframe indel			2			2
splice donor/acceptor (+/-2bp)	2	7				9
splice region	1		9	16	1	27
non coding			25	73	37	135
Total	27	17	150	137	42

Highest pathogenic variant AF is 0.0000394

Variants in AP4M1

This is a list of pathogenic ClinVar variants found in the AP4M1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
7-100101705-C-T		not specified	Likely benign (Mar 10, 2016)
7-100101717-G-C		Hereditary spastic paraplegia 50	Uncertain significance (Dec 11, 2023)
7-100101723-C-A		Hereditary spastic paraplegia 50	Likely benign (Sep 30, 2023)
7-100101724-C-T		Intellectual disability • Hereditary spastic paraplegia 50	Pathogenic/Likely pathogenic (Mar 04, 2022)
7-100101726-A-G		Hereditary spastic paraplegia 50	Likely benign (Aug 09, 2022)
7-100101726-A-T		Hereditary spastic paraplegia 50	Uncertain significance (Mar 18, 2022)
7-100101733-A-C		Inborn genetic diseases	Uncertain significance (Oct 27, 2022)
7-100101740-C-T		Hereditary spastic paraplegia 50	Uncertain significance (Mar 02, 2021)
7-100101743-C-T		Inborn genetic diseases	Uncertain significance (Jul 06, 2022)
7-100101744-C-T		Hereditary spastic paraplegia 50	Likely benign (Apr 24, 2023)
7-100101744-CA-C		Hereditary spastic paraplegia 50 • Intellectual disability	Pathogenic/Likely pathogenic (Sep 13, 2022)
7-100101759-C-G		Hereditary spastic paraplegia 50	Likely benign (Apr 27, 2023)
7-100101759-C-T		Hereditary spastic paraplegia 50	Likely benign (Jan 01, 2022)
7-100101764-ACAAAGACTGTATC-A		Hereditary spastic paraplegia 50	Pathogenic (Sep 13, 2022)
7-100101765-CAA-C		Abnormality of the nervous system	Pathogenic (Jul 10, 2021)
7-100101769-G-A		Hereditary spastic paraplegia 50	Uncertain significance (Jan 13, 2021)
7-100101771-C-T		AP4M1-related disorder	Uncertain significance (May 18, 2023)
7-100101771-CTG-C		Hereditary spastic paraplegia 50	Likely pathogenic (Oct 13, 2023)
7-100101774-T-G		Hereditary spastic paraplegia 50	Likely pathogenic (Nov 29, 2022)
7-100101775-A-G			Uncertain significance (Oct 01, 2021)
7-100101784-C-T		not specified • Hereditary spastic paraplegia 50	Benign (Jan 22, 2024)
7-100101786-T-C		Hereditary spastic paraplegia 50	Likely benign (Jan 18, 2024)
7-100101813-G-A			Benign (Jun 26, 2018)
7-100101863-G-A		Hereditary spastic paraplegia 50	Likely benign (Jul 16, 2022)
7-100101864-T-C		Hereditary spastic paraplegia 50	Likely benign (Jun 04, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
AP4M1	protein_coding	protein_coding	ENST00000359593	15	8797

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
4.49e-17	0.0116	125633	0	115	125748	0.000457

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-1.21	311	256	1.21	0.0000169	2910
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000876	0.000876
Ashkenazi Jewish	0.00	0.00
East Asian	0.000435	0.000435
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.000582	0.000580
Middle Eastern	0.000435	0.000435
South Asian	0.000588	0.000588
Other	0.000489	0.000489

dbNSFP

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}.
• Pathway: Lysosome - Homo sapiens (human);Lysosome Vesicle Biogenesis;Clathrin derived vesicle budding;trans-Golgi Network Vesicle Budding;Vesicle-mediated transport;Membrane Trafficking (Consensus)

Recessive Scores

• pRec: 0.138

Intolerance Scores

• loftool: 0.788
• rvis_EVS: -1.18
• rvis_percentile_EVS: 5.97

Haploinsufficiency Scores

• hipred: Y
• hipred_score: 0.606
• ghis: 0.598

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.973

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Ap4m1
• Phenotype: homeostasis/metabolism phenotype

Gene ontology

• Biological process: protein targeting;protein targeting to lysosome;intracellular protein transport;Golgi to endosome transport;protein localization;Golgi to lysosome transport;protein localization to basolateral plasma membrane
• Cellular component: early endosome;trans-Golgi network;cytosol;AP-4 adaptor complex;clathrin adaptor complex;endosome lumen;trans-Golgi network membrane;extracellular exosome
• Molecular function: protein binding;protein domain specific binding