ADAM17

ADAM metallopeptidase domain 17, the group of ADAM metallopeptidase domain containing|CD molecules

Basic information

Region (hg38): 2:9488485-9556732

Previous symbols: [ "TACE" ]

Links

ENSG00000151694 ∙ NCBI:6868 ∙ OMIM:603639 ∙ HGNC:195 ∙ Uniprot:P78536 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• inflammatory skin and bowel disease, neonatal, 1 (Moderate), mode of inheritance: AR
• neonatal inflammatory skin and bowel disease (Supportive), mode of inheritance: AR
• inflammatory skin and bowel disease, neonatal, 1 (Strong), mode of inheritance: AR
• congenital heart disease (Limited), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Inflammatory skin and bowel disease, neonatal 1	AR	Allergy/Immunology/Infectious; Cardiovascular	Antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial; Individuals may also have cardiovascular manifestations, and surveillance may allow beneficial interventions	Allergy/Immunology/Infectious; Cardiovascular; Dermatologic; Gastrointestinal	22010916

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ADAM17 gene.

• Inflammatory skin and bowel disease, neonatal, 1 (400 variants)
• not provided (62 variants)
• Inborn genetic diseases (20 variants)
• not specified (10 variants)
• Anophthalmia-microphthalmia syndrome (1 variants)
• ADAM17-related condition (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ADAM17 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				91	7	98
missense			185	7	3	195
nonsense	1					1
start loss						0
frameshift	7		10			17
inframe indel			2			2
splice donor/acceptor (+/-2bp)	2	3				5
splice region			12	16	1	29
non coding			1	56	51	108
Total	10	3	198	154	61

Highest pathogenic variant AF is 0.00000818

Variants in ADAM17

This is a list of pathogenic ClinVar variants found in the ADAM17 region.

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

Position	Type	Phenotype	Significance	ClinVar
2-9489887-T-C			Benign (Nov 10, 2018)
2-9490102-C-T		Inflammatory skin and bowel disease, neonatal, 1 • not specified	Benign (Nov 12, 2023)
2-9490115-AT-A		Inflammatory skin and bowel disease, neonatal, 1 • not specified	Benign (Nov 12, 2023)
2-9490180-GCACTCTGTTTCTTTGCTGTCAA-G		Inborn genetic diseases	Uncertain significance (May 10, 2018)
2-9490185-CTG-C		Inflammatory skin and bowel disease, neonatal, 1	Uncertain significance (Oct 22, 2021)
2-9490185-C-CTGT		Inflammatory skin and bowel disease, neonatal, 1	Uncertain significance (Feb 20, 2020)
2-9490200-C-G		Inflammatory skin and bowel disease, neonatal, 1	Uncertain significance (Feb 24, 2022)
2-9490206-G-A		Inflammatory skin and bowel disease, neonatal, 1	Uncertain significance (Sep 01, 2021)
2-9490206-G-GA		Inflammatory skin and bowel disease, neonatal, 1	Uncertain significance (Apr 23, 2021)
2-9490208-T-C		Inflammatory skin and bowel disease, neonatal, 1	Uncertain significance (Feb 05, 2022)
2-9490214-C-T		Inflammatory skin and bowel disease, neonatal, 1 • Inborn genetic diseases	Uncertain significance (Nov 03, 2023)
2-9490215-G-A		Inflammatory skin and bowel disease, neonatal, 1 • Inborn genetic diseases	Uncertain significance (Jan 23, 2024)
2-9490227-A-G		Inflammatory skin and bowel disease, neonatal, 1	Uncertain significance (Apr 27, 2021)
2-9490236-C-A		Inflammatory skin and bowel disease, neonatal, 1	Uncertain significance (Dec 15, 2021)
2-9490236-C-G		Inflammatory skin and bowel disease, neonatal, 1	Uncertain significance (Oct 13, 2023)
2-9490237-C-CT		Inflammatory skin and bowel disease, neonatal, 1	Uncertain significance (Feb 10, 2022)
2-9490241-T-C		Inflammatory skin and bowel disease, neonatal, 1	Uncertain significance (Apr 18, 2022)
2-9490247-C-G		Inborn genetic diseases	Uncertain significance (Dec 30, 2023)
2-9490254-C-A		Inflammatory skin and bowel disease, neonatal, 1	Uncertain significance (Jan 28, 2019)
2-9490255-C-T		Inflammatory skin and bowel disease, neonatal, 1	Likely benign (Jan 16, 2022)
2-9490256-G-A		Inflammatory skin and bowel disease, neonatal, 1	Uncertain significance (Aug 27, 2021)
2-9490261-GT-G		Inflammatory skin and bowel disease, neonatal, 1	Uncertain significance (Jul 02, 2021)
2-9490263-C-A		Inflammatory skin and bowel disease, neonatal, 1	Uncertain significance (Jul 03, 2023)
2-9490264-C-T		Inflammatory skin and bowel disease, neonatal, 1	Likely benign (Oct 28, 2021)
2-9490269-G-C		Inflammatory skin and bowel disease, neonatal, 1	Uncertain significance (Aug 15, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ADAM17	protein_coding	protein_coding	ENST00000310823	19	67307

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.995	0.00472	125709	0	39	125748	0.000155

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.45	305	452	0.675	0.0000237	5500
Missense in Polyphen		55	149.71	0.36738		1847
Synonymous	-0.0628	171	170	1.01	0.00000997	1468
Loss of Function	5.17	6	42.3	0.142	0.00000205	546

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000123	0.000123
Ashkenazi Jewish	0.00	0.00
East Asian	0.000167	0.000163
Finnish	0.000508	0.000508
European (Non-Finnish)	0.000176	0.000176
Middle Eastern	0.000167	0.000163
South Asian	0.0000998	0.0000980
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Cleaves the membrane-bound precursor of TNF-alpha to its mature soluble form (PubMed:9034191). 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 p75 TNF- receptor, interleukin 1 receptor type II, p55 TNF-receptor, transforming growth factor-alpha, L-selectin, growth hormone receptor, MUC1 and the amyloid precursor protein (PubMed:12441351). Acts as an activator of Notch pathway by mediating cleavage of Notch, generating the membrane-associated intermediate fragment called Notch extracellular truncation (NEXT) (PubMed:24226769). Plays a role in the proteolytic processing of ACE2 (PubMed:24227843). {ECO:0000269|PubMed:12441351, ECO:0000269|PubMed:20592283, ECO:0000269|PubMed:24226769, ECO:0000269|PubMed:24227843, ECO:0000269|PubMed:9034191}.
• Disease: DISEASE: Inflammatory skin and bowel disease, neonatal, 1 (NISBD1) [MIM:614328]: A disorder characterized by inflammatory features with neonatal onset, involving the skin, hair, and gut. The skin lesions involve perioral and perianal erythema, psoriasiform erythroderma, with flares of erythema, scaling, and widespread pustules. Gastrointestinal symptoms include malabsorptive diarrhea that is exacerbated by intercurrent gastrointestinal infections. The hair is short or broken, and the eyelashes and eyebrows are wiry and disorganized. {ECO:0000269|PubMed:22010916}. Note=The disease is caused by mutations 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 signaling pathway - Homo sapiens (human);NOTCH-Ncore;Alzheimers Disease;Brain-Derived Neurotrophic Factor (BDNF) signaling pathway;Notch Signaling Pathway;Copper homeostasis;Ebola Virus Pathway on Host;Ebola Virus Pathway on Host;Notch Signaling Pathway;Notch Signaling Pathway;Disease;Signal Transduction;Growth hormone receptor signaling;proteolysis and signaling pathway of notch;segmentation clock;g-secretase mediated erbb4 signaling pathway;Cytokine Signaling in Immune system;Collagen degradation;Extracellular matrix organization;DroToll-like;Receptor-ligand binding initiates the second proteolytic cleavage of Notch receptor;Notch;Immune System;Signaling by NOTCH1;Signaling by NOTCH;ErbB4 signaling events;Release of Hh-Np from the secreting cell;Hedgehog ligand biogenesis;Signaling by EGFR;Signaling by Hedgehog;EGFR1;TNF signaling;Degradation of the extracellular matrix;Death Receptor Signalling;Regulated proteolysis of p75NTR;p75 NTR receptor-mediated signalling;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;Nuclear signaling by ERBB4;Signaling by ERBB4;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;TNF receptor signaling pathway ;Diseases of signal transduction;p75(NTR)-mediated signaling;Activated NOTCH1 Transmits Signal to the Nucleus (Consensus)

Recessive Scores

• pRec: 0.381

Intolerance Scores

• loftool: 0.287
• rvis_EVS: 0.6
• rvis_percentile_EVS: 82.78

Haploinsufficiency Scores

• pHI: 0.262
• hipred: Y
• hipred_score: 0.825
• ghis: 0.438

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.970

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Adam17
• Phenotype: homeostasis/metabolism phenotype; cellular phenotype; muscle phenotype; growth/size/body region phenotype; 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); endocrine/exocrine gland phenotype; respiratory system phenotype; immune system phenotype; skeleton 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); 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); 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); normal phenotype; reproductive system phenotype; pigmentation phenotype; embryo phenotype

Gene ontology

• Biological process: response to hypoxia;positive regulation of protein phosphorylation;neutrophil mediated immunity;germinal center formation;positive regulation of leukocyte chemotaxis;proteolysis;membrane protein ectodomain proteolysis;cell adhesion;epidermal growth factor receptor signaling pathway;Notch signaling pathway;Notch receptor processing;positive regulation of cell population proliferation;positive regulation of T cell chemotaxis;B cell differentiation;positive regulation of cell growth;positive regulation of cell migration;positive regulation of transforming growth factor beta receptor signaling pathway;negative regulation of transforming growth factor beta receptor signaling pathway;membrane protein intracellular domain proteolysis;response to lipopolysaccharide;positive regulation of chemokine production;regulation of mast cell apoptotic process;T cell differentiation in thymus;tumor necrosis factor-mediated signaling pathway;cell adhesion mediated by integrin;wound healing, spreading of epidermal cells;receptor transactivation;response to drug;positive regulation of blood vessel endothelial cell migration;positive regulation of epidermal growth factor-activated receptor activity;spleen development;cell motility;defense response to Gram-positive bacterium;PMA-inducible membrane protein ectodomain proteolysis;positive regulation of cellular component movement;cellular response to high density lipoprotein particle stimulus;negative regulation of cold-induced thermogenesis;positive regulation of tumor necrosis factor-mediated signaling pathway;positive regulation of vascular endothelial cell proliferation
• Cellular component: cytoplasm;cytosol;plasma membrane;integral component of plasma membrane;cell-cell junction;focal adhesion;cell surface;actin cytoskeleton;membrane;apical plasma membrane;ruffle membrane;membrane raft
• Molecular function: endopeptidase activity;metalloendopeptidase activity;Notch binding;interleukin-6 receptor binding;integrin binding;protein binding;peptidase activity;metallopeptidase activity;SH3 domain binding;PDZ domain binding;metal ion binding