ADAM17

Chr 2

ADAM metallopeptidase domain 17

Also known as: ADAM18, CD156B, CSVP, HYPT16, NISBD, NISBD1, TACE

NCBI Gene: 6868 ENSG00000151694 UniProt: P78536

This gene encodes a member of the ADAM (a disintegrin and metalloprotease domain) family. Members of this family are membrane-anchored proteins structurally related to snake venom disintegrins, and have been implicated in a variety of biologic processes involving cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis. The encoded preproprotein is proteolytically processed to generate the mature protease. The encoded protease functions in the ectodomain shedding of tumor necrosis factor-alpha, in which soluble tumor necrosis factor-alpha is released from the membrane-bound precursor. This protease also functions in the processing of numerous other substrates, including cell adhesion proteins, cytokine and growth factor receptors and epidermal growth factor (EGF) receptor ligands, and plays a prominent role in the activation of the Notch signaling pathway. Elevated expression of this gene has been observed in specific cell types derived from psoriasis, rheumatoid arthritis, multiple sclerosis and Crohn's disease patients, suggesting that the encoded protein may play a role in autoimmune disease. Additionally, this protease may play a role in viral infection through its cleavage of ACE2, the cellular receptor for SARS-CoV and SARS-CoV-2. [provided by RefSeq, Aug 2020]

Research

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtHypotrichosis 16

UniProtInflammatory skin and bowel disease, neonatal, 1

Clinical highlights

Gene–disease validity (ClinGen)

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

246

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.28

LOEUF· LoF intol.

—

Mechanism

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.28LOEUF

pLI 0.995

Z-score 5.17

OE 0.14 (0.08–0.28)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.45Z-score

OE missense 0.68 (0.61–0.74)

305 obs / 451.6 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.14 (0.08–0.28)

0≤0.351.4

Missense OE?0.68 (0.61–0.74)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 6 / 42.3Missense obs/exp: 305 / 451.6Syn Z: -0.06

Background carrier burden — how many people carry a rare variant somewhere in ADAM17?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 70

856 rare PASS variants

Rare truncating (LoF)

1 in 1,700

109 rare PASS variants

Rare synonymous (reference)

1 in 120

371 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ADAM17. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 78	1 in 1,500
South Asian	~43k	1 in 62	1 in 5,300
Remaining (unassigned)	~30k	1 in 69	1 in 3,000
European (Finnish)	~27k	1 in 260	1 in 920
Admixed American	~22k	1 in 71	1 in 1,600
African / African American	~21k	1 in 80	1 in 1,900
East Asian	~20k	1 in 72	1 in 1,500
Ashkenazi Jewish	~13k	1 in 190	≈ 1 in 3,500
Middle Eastern	~2,884	1 in 69	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 15 of 19 coding exons well covered in gnomAD exomes; exons 4, 5, 8, 9 marginal. Genomes: 18 of 19 (exon 9 below).? see exons ↓