ADAMTS2

protein-coding

ADAM metallopeptidase with thrombospondin type 1 motif 2, the group of ADAM metallopeptidases with thrombospondin type 1 motif

Gene summary

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 procollagen N-proteinase. This proteinase excises the N-propeptide of the fibrillar procollagens types I-III and type V. Mutations in this gene cause Ehlers-Danlos syndrome type VIIC, a recessively inherited connective-tissue disorder. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Feb 2016]

MANE transcript

NM_014244.5

Inheritance

ClinVar variants

P:339U:601B:726

Top phenotype

Ehlers-Danlos syndrome, dermatosparaxis type

gnomAD constraint

pLI —, LoF o/e 0.18

Max pathogenic AF

—

Genomic locus

chr5:179,110,853-179,345,461

External References & Databases

Ensembl (ENSG00000087116)

Transcript & Mutation Effects

hg38 • Region Span ~234.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Ehlers-Danlos syndrome, dermatosparaxis typeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009161

Submitter: PanelApp Australia

Ehlers-Danlos syndrome, dermatosparaxis typeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009161

Submitter: Labcorp Genetics (formerly Invitae)

Ehlers-Danlos syndrome, dermatosparaxis typeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009161

Submitter: G2P

Ehlers-Danlos syndrome, dermatosparaxis typeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009161

Submitter: Illumina

Ehlers-Danlos syndrome, dermatosparaxis typeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009161

Submitter: Natera

Ehlers-Danlos syndrome, dermatosparaxis typeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009161

Submitter: Orphanet

Ehlers-Danlos syndrome, dermatosparaxis typeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009161

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Ehlers-Danlos syndrome, dermatosparaxis typeAR

Manifestation: Craniofacial; Dermatologic; Musculoskeletal; Obstetric

Intervention: Obstetric

Rationale: Individuals may be prone to injuries (especially during delivery, as multiple congenital skull fractures and intracranial hemorrhage have been reported), and knowledge may allow delivery-based interventions to decrease related morbidity and mortality

Refs: 1303238; 8215497; 7735500; 10417273; 15373769; 15389701; 18973246

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ADAMTS2 variants in ClinVar

7 Conditions Cataloged

Ehlers-Danlos syndrome, dermatosparaxis typeTotal: 1861

not providedTotal: 383

not specifiedTotal: 329

Inborn genetic diseasesTotal: 196

Ehlers-Danlos syndromeTotal: 71

ADAMTS2-related disorderTotal: 61

See casesTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014244.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			26 clinvar	670 clinvar	7 clinvar	703
missense		1 clinvar	567 clinvar	46 clinvar	1 clinvar	615
nonsense	28 clinvar	18 clinvar	2 clinvar			48
start loss		2 clinvar				2
frameshift	230 clinvar	43 clinvar	6 clinvar			279
splice donor/acceptor (+/-2bp)		17 clinvar			2 clinvar	19
Total	258	81	601	716	10	1666

Highest pathogenic variant AF is 0.00007825902

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 17 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014244.5	RefSeq	NP_055059.2	22	MANE Select
ENST00000251582.12	Ensembl	ENSP00000251582.7	22	MANE Select
NM_021599.4	RefSeq	NP_067610.1	11	Standard
ENST00000274609.5	Ensembl	ENSP00000274609.5	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Collagen biosynthesis and modifying enzymes
Post-translational protein modification
Metabolism of proteins
Collagen formation
Extracellular matrix organization

Biological Process

spermatogenesis
protein processing
collagen fibril organization
lung development
collagen catabolic process

Molecular Function

metalloendopeptidase activity
metallopeptidase activity
zinc ion binding

Cellular Component

extracellular region
collagen-containing extracellular matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000251582
Coding exons: 22
Length: 234580
Individuals with no LoFs: 125665
Homozygous LoFs: 0
Heterozygous LoFs: 83
Defined: 125748
p: 0.000330

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.43	637	747	0.853	0.0000518	7846
Missense (PolyPhen)		212	326.2	0.64991		3393
Synonymous	-0.390	320	311	1.03	0.0000233	2391
Loss of Function	5.59	10	54.6	0.183	0.00000275	617

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00017	0.00017	rare
Ashkenazi Jewish	0.0030	0.0030	notable
East Asian	0.00028	0.00027	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00024	0.00024	rare
South Asian	0.00036	0.00036	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Cleaves the propeptides of type I and II collagen prior to fibril assembly. Does not act on type III collagen. May also play a role in development that is independent of its role in collagen biosynthesis.;
Disease: DISEASE: Ehlers-Danlos syndrome, dermatosparaxis type (EDSDERMS) [MIM:225410]: A form of Ehlers-Danlos syndrome, a group of connective tissue disorders characterized by skin hyperextensibility, articular hypermobility, and tissue fragility. EDSDERMS is an autosomal recessive form characterized by extreme skin fragility and easy bruising, large fontanels, blue sclerae, puffy eyelids, micrognathia, umbilical hernia, and short fingers. Joint hypermobility becomes more important with age. {ECO:0000269|PubMed:10417273}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.315

Intolerance Scores

LoFtool: 0.135
RVIS EVS: -1.8
RVIS percentile EVS: 2.22

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.213

Gene Damage Prediction

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