ADAM15

Chr 1

ADAM metallopeptidase domain 15

Also known as: MDC15

NCBI Gene: 8751 ENSG00000143537 UniProt: Q13444 OMIM: 605548

The protein encoded by this gene is a member of the ADAM (a disintegrin and metalloproteinase) protein family. ADAM family members are type I transmembrane glycoproteins known to be involved in cell adhesion and proteolytic ectodomain processing of cytokines and adhesion molecules. This protein contains multiple functional domains including a zinc-binding metalloprotease domain, a disintegrin-like domain, as well as a EGF-like domain. Through its disintegrin-like domain, this protein specifically interacts with the integrin beta chain, beta 3. It also interacts with Src family protein-tyrosine kinases in a phosphorylation-dependent manner, suggesting that this protein may function in cell-cell adhesion as well as in cellular signaling. Multiple alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2008]

OMIM Research

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.86

Clinical Summary— ADAM15

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

129 VUS of 205 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.86LOEUF

pLI 0.000

Z-score 2.35

OE 0.65 (0.49–0.86)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.07Z-score

OE missense 0.87 (0.80–0.94)

433 obs / 500.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.65 (0.49–0.86)

0≤0.351.4

Missense OE?0.87 (0.80–0.94)

0≤0.61.4

Synonymous OE?0.87

0≤1.21.6

LoF obs/exp: 33 / 51.1Missense obs/exp: 433 / 500.3Syn Z: 1.42

This gene — mechanism propensity

0.6745th %ile

GOF

0.6832th %ile

LOF

0.3068th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

205 submitted variants in ClinVar

ClinVar

Classification Summary

VUS129

Likely Benign16

Benign2

129

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	129	0	0	129
Likely Benign	14	0	2	16
Benign	1	1	0	2
Total	144	1	2	147

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

14 pathogenic / likely-pathogenic (of 19) ClinVar copy-number / structural variants overlap ADAM15 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →