AP4E1

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

Basic information

Region (hg38): 15:50908671-51005895

Links

ENSG00000081014 ∙ NCBI:23431 ∙ OMIM:607244 ∙ HGNC:573 ∙ Uniprot:Q9UPM8 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hereditary spastic paraplegia 51 (Definitive), mode of inheritance: AR
• hereditary spastic paraplegia 51 (Moderate), mode of inheritance: AR
• hereditary spastic paraplegia 51 (Strong), mode of inheritance: AR
• AP4-related intellectual disability and spastic paraplegia (Supportive), 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
Stuttering, familial persistent, 1; Spastic paraplegia 51, autosomal recessive	AD/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	Craniofacial; Neurologic	21620353; 20972249; 21937992; 24700674; 26544806

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the AP4E1 gene.

• Spastic paraplegia (338 variants)
• not provided (110 variants)
• not specified (50 variants)
• Inborn genetic diseases (33 variants)
• Hereditary spastic paraplegia 51 (31 variants)
• Hereditary spastic paraplegia (30 variants)
• Stuttering, familial persistent, 1 (21 variants)
• Hereditary spastic paraplegia 51;Stuttering, familial persistent, 1 (3 variants)
• Stuttering, familial persistent, 1;Hereditary spastic paraplegia 51 (2 variants)
• AP4E1-related condition (1 variants)
• ALG12-congenital disorder of glycosylation (1 variants)
• Neurodevelopmental delay (1 variants)
• - (1 variants)
• Abnormality of the nervous system (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the AP4E1 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			9	76	2	87
missense			214	8	2	224
nonsense	2	3				5
start loss			1			1
frameshift	4	1				5
inframe indel			2			2
splice donor/acceptor (+/-2bp)		2	1			3
splice region	1	1	5	7	3	17
non coding			10	64	42	116
Total	6	6	237	148	46

Highest pathogenic variant AF is 0.00000658

Variants in AP4E1

This is a list of pathogenic ClinVar variants found in the AP4E1 region.

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

Position	Type	Phenotype	Significance	ClinVar
15-50908732-C-A		not specified	Likely benign (Aug 09, 2016)
15-50908739-G-A		not specified	Likely benign (Dec 21, 2017)
15-50908741-G-GATCGCGGGCGGCGGCGGC		not specified • AP4E1-related disorder	Likely benign (Aug 30, 2023)
15-50908776-G-T		not specified	Uncertain significance (Dec 02, 2016)
15-50908780-T-C		not specified	Uncertain significance (Sep 07, 2022)
15-50908803-C-G		Spastic paraplegia	Uncertain significance (May 04, 2022)
15-50908807-C-T		Spastic paraplegia	Uncertain significance (Nov 27, 2023)
15-50908808-G-A		Spastic paraplegia	Likely benign (Nov 27, 2023)
15-50908808-G-T		Spastic paraplegia	Likely benign (Feb 04, 2022)
15-50908811-G-A		Spastic paraplegia	Likely benign (Aug 22, 2022)
15-50908820-A-G		not specified • Spastic paraplegia • AP4E1-related disorder	Likely benign (Mar 20, 2022)
15-50908824-T-C		Spastic paraplegia	Uncertain significance (Feb 05, 2022)
15-50908843-G-A		Inborn genetic diseases	Uncertain significance (Aug 30, 2021)
15-50908845-G-A		Spastic paraplegia	Uncertain significance (May 13, 2022)
15-50908845-G-C		Spastic paraplegia	Uncertain significance (Aug 06, 2020)
15-50908846-G-T		Spastic paraplegia	Uncertain significance (Jan 12, 2022)
15-50908864-A-C		Spastic paraplegia	Uncertain significance (Apr 20, 2023)
15-50908871-C-T		Spastic paraplegia	Likely benign (May 25, 2022)
15-50908882-G-A		Hereditary spastic paraplegia	Uncertain significance (Apr 11, 2021)
15-50908888-G-T			Uncertain significance (Feb 10, 2021)
15-50908899-C-A		Spastic paraplegia	Uncertain significance (Jun 15, 2022)
15-50908910-A-T		Spastic paraplegia	Likely benign (Jul 27, 2020)
15-50908911-G-A		Spastic paraplegia	Uncertain significance (Aug 10, 2023)
15-50908914-C-G		Spastic paraplegia	Uncertain significance (Feb 08, 2022)
15-50908916-C-T		Spastic paraplegia	Likely benign (Apr 05, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
AP4E1	protein_coding	protein_coding	ENST00000261842	21	97229

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00275	0.997	125662	0	86	125748	0.000342

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.521	532	567	0.938	0.0000260	7414
Missense in Polyphen		171	203.74	0.8393		2737
Synonymous	-0.490	223	214	1.04	0.0000105	2162
Loss of Function	4.98	16	56.3	0.284	0.00000277	751

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000211	0.000210
Ashkenazi Jewish	0.000299	0.000298
East Asian	0.000218	0.000217
Finnish	0.000143	0.000139
European (Non-Finnish)	0.000380	0.000378
Middle Eastern	0.000218	0.000217
South Asian	0.000882	0.000882
Other	0.000163	0.000163

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: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}.
• Disease: DISEASE: Stuttering, familial persistent 1 (STUT1) [MIM:184450]: A familial form of stuttering, a disturbance in the normal fluency and time patterning of speech, characterized by frequent repetitions or prolongations of sounds or syllables, and by interruptions of speech known as blocks. STUT1 inheritance is autosomal dominant. {ECO:0000269|PubMed:26544806}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Lysosome - Homo sapiens (human);Golgi Associated Vesicle Biogenesis;Lysosome Vesicle Biogenesis;Clathrin derived vesicle budding;trans-Golgi Network Vesicle Budding;Vesicle-mediated transport;Membrane Trafficking (Consensus)

Recessive Scores

• pRec: 0.0996

Intolerance Scores

• loftool: 0.691
• rvis_EVS: -0.66
• rvis_percentile_EVS: 16.07

Haploinsufficiency Scores

• pHI: 0.454
• hipred: Y
• hipred_score: 0.579
• ghis: 0.551

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.639

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Ap4e1
• Phenotype: homeostasis/metabolism phenotype; muscle phenotype; growth/size/body region phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); immune system phenotype; renal/urinary system phenotype; skeleton phenotype; hearing/vestibular/ear phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); limbs/digits/tail phenotype; vision/eye phenotype; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan)

Gene ontology

• Biological process: protein targeting;protein localization;vesicle-mediated transport
• Cellular component: AP-4 adaptor complex;endosome lumen;trans-Golgi network membrane
• Molecular function: protein binding