ADAMTS3

Chr 4AR

ADAM metallopeptidase with thrombospondin type 1 motif 3

Also known as: ADAMTS-4, HKLLS3

NCBI Gene: 9508 ENSG00000156140 UniProt: O15072 OMIM: 605011

This protein cleaves propeptides of type II collagen prior to fibril assembly and does not act on types I and III collagens. Mutations cause Hennekam lymphangiectasia-lymphedema syndrome 3, which involves lymphatic abnormalities and connective tissue defects. The gene follows autosomal recessive inheritance and shows minimal constraint against loss-of-function variants (very low pLI score).

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family. Members of the family share several distinct protein modules, including a propeptide region, a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. Individual members of this family differ in the number of C-terminal TS motifs, and some have unique C-terminal domains. The encoded preproprotein is proteolytically processed to generate the mature protease. This protease, a member of the procollagen aminopropeptidase subfamily of proteins, may play a role in the processing of type II fibrillar collagen in articular cartilage. [provided by RefSeq, Feb 2016]

OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 0.601 OMIM phenotype

Clinical Summary— ADAMTS3

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Population Constraint (gnomAD)

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

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ClinVar Variants

3 unique Pathogenic / Likely Pathogenic· 173 VUS of 231 total submissions

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

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?

0.60LOEUF

pLI 0.000

Z-score 4.13

OE 0.44 (0.33–0.60)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.55Z-score

OE missense 0.94 (0.88–1.00)

641 obs / 681.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.44 (0.33–0.60)

0≤0.351.4

Missense OE?0.94 (0.88–1.00)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 28 / 63.5Missense obs/exp: 641 / 681.0Syn Z: 0.38

This gene — mechanism propensity

0.6454th %ile

GOF

0.5661th %ile

LOF

0.3355th %ile

The highest-scoring mechanism for this gene is dominant-negative.

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

231 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

VUS173

Likely Benign30

Benign16

Conflicting3

Pathogenic

173

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	2	0	0	3
Likely Pathogenic	0	0	0	0	0
VUS	1	171	1	0	173
Likely Benign	0	7	3	20	30
Benign	0	8	5	3	16
Conflicting	—				3
Total	2	188	9	23	225

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

View in ClinVar →

26 pathogenic / likely-pathogenic (of 34) ClinVar copy-number / structural variants overlap ADAMTS3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →