ADAM10

ADAM metallopeptidase domain 10, the group of ADAM metallopeptidase domain containing|CD molecules

Basic information

Region (hg38): 15:58588808-58749791

Links

ENSG00000137845 ∙ NCBI:102 ∙ OMIM:602192 ∙ HGNC:188 ∙ Uniprot:O14672 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• reticulate acropigmentation of Kitamura (Moderate), mode of inheritance: AD
• reticulate acropigmentation of Kitamura (Supportive), mode of inheritance: AD
• reticulate acropigmentation of Kitamura (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Reticulate acropigmentation of Kitamura	AD	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	Dermatologic	23666529

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ADAM10 gene.

• not provided (26 variants)
• Inborn genetic diseases (17 variants)
• - (2 variants)
• Reticulate acropigmentation of Kitamura (2 variants)
• Alzheimer disease 18;Reticulate acropigmentation of Kitamura (1 variants)
• not specified (1 variants)
• Alzheimer disease 18 (1 variants)
• Corticobasal syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ADAM10 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				1	2	3
missense			21			21
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region					1	1
non coding				1	21	22
Total	0	0	21	2	23

Variants in ADAM10

This is a list of pathogenic ClinVar variants found in the ADAM10 region.

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

Position	Type	Phenotype	Significance	ClinVar
15-58597552-G-A		Inborn genetic diseases	Uncertain significance (Feb 05, 2024)
15-58597588-G-A		Inborn genetic diseases	Uncertain significance (Oct 14, 2023)
15-58597594-G-A		Inborn genetic diseases	Uncertain significance (Jun 24, 2022)
15-58597594-G-T		Inborn genetic diseases	Uncertain significance (May 17, 2023)
15-58597608-A-G		Inborn genetic diseases	Uncertain significance (Dec 15, 2023)
15-58599318-T-TA			Benign (Jun 18, 2021)
15-58599707-T-C		ADAM10-related disorder	Benign (Oct 28, 2019)
15-58599724-C-T		Reticulate acropigmentation of Kitamura	Uncertain significance (Feb 22, 2023)
15-58599750-GA-G			Benign (Jun 18, 2021)
15-58599899-T-A			Benign (Jun 18, 2021)
15-58610332-G-A		Inborn genetic diseases	Uncertain significance (Feb 11, 2022)
15-58610440-G-A		Inborn genetic diseases	Uncertain significance (Mar 20, 2023)
15-58610517-A-G		Inborn genetic diseases	Uncertain significance (Nov 29, 2023)
15-58610570-A-C			Benign (Nov 10, 2018)
15-58610884-A-G			Benign (Nov 10, 2018)
15-58611056-C-G		Inborn genetic diseases	Uncertain significance (Sep 20, 2023)
15-58611068-C-T		Inborn genetic diseases	Uncertain significance (Nov 10, 2022)
15-58611090-G-C		Inborn genetic diseases	Uncertain significance (Feb 21, 2024)
15-58611092-T-C		Inborn genetic diseases	Uncertain significance (Jan 10, 2023)
15-58611812-T-C		Inborn genetic diseases	Uncertain significance (Sep 01, 2021)
15-58611854-G-T		Inborn genetic diseases	Uncertain significance (Jul 12, 2022)
15-58611932-C-T		Reticulate acropigmentation of Kitamura	Pathogenic (Sep 01, 2013)
15-58612038-C-T			Benign (Nov 10, 2018)
15-58621262-CA-C			Benign (Jun 18, 2021)
15-58621262-CAAAAAAAA-C			Benign (Jun 18, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ADAM10	protein_coding	protein_coding	ENST00000260408	16	154775

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.00000247	125716	0	2	125718	0.00000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.31	222	410	0.541	0.0000210	4967
Missense in Polyphen		14	96.364	0.14528		1173
Synonymous	-0.633	145	136	1.07	0.00000670	1345
Loss of Function	5.75	1	40.5	0.0247	0.00000215	498

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000176	0.0000176
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Cleaves the membrane-bound precursor of TNF-alpha at '76-Ala-|-Val-77' to its mature soluble form. Responsible for the proteolytical release of soluble JAM3 from endothelial cells surface (PubMed:20592283). Responsible for the proteolytic release of several other cell-surface proteins, including heparin-binding epidermal growth-like factor, ephrin-A2, CD44, CDH2 and for constitutive and regulated alpha-secretase cleavage of amyloid precursor protein (APP) (PubMed:26686862, PubMed:11786905, PubMed:29224781). Contributes to the normal cleavage of the cellular prion protein (PubMed:11477090). Involved in the cleavage of the adhesion molecule L1 at the cell surface and in released membrane vesicles, suggesting a vesicle-based protease activity (PubMed:12475894). Controls also the proteolytic processing of Notch and mediates lateral inhibition during neurogenesis (By similarity). Responsible for the FasL ectodomain shedding and for the generation of the remnant ADAM10-processed FasL (FasL APL) transmembrane form (PubMed:17557115). Also cleaves the ectodomain of the integral membrane proteins CORIN and ITM2B (PubMed:19114711, PubMed:21288900). May regulate the EFNA5-EPHA3 signaling (PubMed:16239146). {ECO:0000250|UniProtKB:O35598, ECO:0000269|PubMed:11477090, ECO:0000269|PubMed:11786905, ECO:0000269|PubMed:12475894, ECO:0000269|PubMed:16239146, ECO:0000269|PubMed:17557115, ECO:0000269|PubMed:19114711, ECO:0000269|PubMed:20592283, ECO:0000269|PubMed:21288900, ECO:0000269|PubMed:26686862, ECO:0000269|PubMed:29224781}.
• Disease: DISEASE: Reticulate acropigmentation of Kitamura (RAK) [MIM:615537]: A rare cutaneous pigmentation disorder characterized by reticulate, slightly depressed, sharply demarcated brown macules without hypopigmentation, affecting the dorsa of the hands and feet and appearing in the first or second decade of life. The macules gradually darken and extend to the proximal regions of the extremities. The manifestations tend to progress until middle age, after which progression of the eruptions stops. The pigmentary augmentation is found on the flexor aspects of the wrists, neck, patella and olecranon. Other features include breaks in the epidermal ridges on the palms and fingers, palmoplantar pits, occasionally plantar keratoderma, and partial alopecia. {ECO:0000269|PubMed:23666529}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Alzheimer disease 18 (AD18) [MIM:615590]: A late-onset form of Alzheimer disease. Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituents of these plaques are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, that are produced by the proteolysis of the transmembrane APP protein. The cytotoxic C- terminal fragments (CTFs) and the caspase-cleaved products, such as C31, are also implicated in neuronal death. {ECO:0000269|PubMed:19608551, ECO:0000269|PubMed:24055016}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.
• Pathway: Alzheimer,s disease - Homo sapiens (human);Epithelial cell signaling in Helicobacter pylori infection - Homo sapiens (human);NOTCH-Ncore;Alzheimers Disease;Copper homeostasis;Canonical and Non-canonical Notch signaling;Hypertrophy Model;Neutrophil degranulation;Disease;Signal Transduction;generation of amyloid b-peptide by ps1;Post-translational protein phosphorylation;Post-translational protein modification;Collagen degradation;Metabolism of proteins;Extracellular matrix organization;DroToll-like;Receptor-ligand binding initiates the second proteolytic cleavage of Notch receptor;Notch;Innate Immune System;Immune System;Signaling by NOTCH1;Signaling by NOTCH2;NOTCH3 Activation and Transmission of Signal to the Nucleus;Signaling by NOTCH3;Signaling by NOTCH4;Signaling by NOTCH;Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs);Signaling by EGFR;NOTCH2 Activation and Transmission of Signal to the Nucleus;Degradation of the extracellular matrix;Posttranslational regulation of adherens junction stability and dissassembly;Notch signaling pathway;Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant;Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant;Constitutive Signaling by NOTCH1 HD Domain Mutants;Signaling by NOTCH1 HD Domain Mutants in Cancer;Constitutive Signaling by NOTCH1 PEST Domain Mutants;Signaling by NOTCH1 PEST Domain Mutants in Cancer;Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants;Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer;Signaling by NOTCH1 in Cancer;Signaling by Receptor Tyrosine Kinases;Diseases of signal transduction;Presenilin action in Notch and Wnt signaling;Activated NOTCH1 Transmits Signal to the Nucleus (Consensus)

Recessive Scores

• pRec: 0.375

Intolerance Scores

• loftool: 0.206
• rvis_EVS: -0.38
• rvis_percentile_EVS: 27.69

Haploinsufficiency Scores

• pHI: 0.990
• hipred: Y
• hipred_score: 0.825
• ghis: 0.644

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.988

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Adam10
• Phenotype: digestive/alimentary 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); skeleton phenotype; immune system phenotype; embryo phenotype; pigmentation 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); growth/size/body region phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); normal phenotype; craniofacial phenotype; homeostasis/metabolism phenotype; cellular phenotype; endocrine/exocrine gland phenotype

Gene ontology

• Biological process: in utero embryonic development;protein phosphorylation;membrane protein ectodomain proteolysis;negative regulation of cell adhesion;Notch signaling pathway;integrin-mediated signaling pathway;cell-cell signaling;spermatogenesis;positive regulation of cell population proliferation;positive regulation of T cell chemotaxis;protein processing;extracellular matrix disassembly;positive regulation of cell growth;positive regulation of cell migration;amyloid-beta formation;response to tumor necrosis factor;Notch receptor processing, ligand-dependent;monocyte activation;positive regulation of apoptotic process;neutrophil degranulation;post-translational protein modification;cellular protein metabolic process;PMA-inducible membrane protein ectodomain proteolysis;constitutive protein ectodomain proteolysis;regulation of dendritic spine morphogenesis;response to antineoplastic agent;regulation of neurotransmitter receptor localization to postsynaptic specialization membrane;postsynapse organization
• Cellular component: Golgi membrane;nucleus;cytoplasm;endoplasmic reticulum lumen;Golgi apparatus;Golgi-associated vesicle;trans-Golgi network;plasma membrane;focal adhesion;synaptic vesicle;cell surface;postsynaptic density;membrane;integral component of membrane;specific granule membrane;neuronal cell body;dendritic spine;postsynaptic membrane;extracellular exosome;tertiary granule membrane;perinuclear endoplasmic reticulum;tetraspanin-enriched microdomain;glutamatergic synapse
• Molecular function: endopeptidase activity;metalloendopeptidase activity;signaling receptor binding;integrin binding;protein binding;metallopeptidase activity;SH3 domain binding;protein kinase binding;protein homodimerization activity;metal ion binding