ADAMTS13

protein-coding

ADAM metallopeptidase with thrombospondin type 1 motif 13, the group of ADAM metallopeptidases with thrombospondin type 1 motif

Gene summary

This gene encodes a member of a family of proteins containing several distinct regions, including a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. The enzyme encoded by this gene specifically cleaves von Willebrand Factor (vWF). Defects in this gene are associated with thrombotic thrombocytopenic purpura. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

Previous symbols:

C9orf8

MANE transcript

NM_139027.6

Inheritance

ClinVar variants

P:149U:459B:275

Top phenotype

Thrombotic thrombocytopenic purpura, hereditary (Schulman-Upshaw syndrome)

gnomAD constraint

pLI —, LoF o/e 0.52

Max pathogenic AF

—

Genomic locus

chr9:133,414,358-133,459,402

External References & Databases

Ensembl (ENSG00000160323)

Transcript & Mutation Effects

hg38 • Region Span ~45.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital thrombotic thrombocytopenic purpuraSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010122

Submitter: Labcorp Genetics (formerly Invitae)

congenital thrombotic thrombocytopenic purpuraSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010122

Submitter: Genomics England PanelApp

congenital thrombotic thrombocytopenic purpuraSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010122

Submitter: Orphanet

congenital thrombotic thrombocytopenic purpuraDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010122

Submitter: ClinGen

ADAMTS13 was first reported in relation to autosomal recessive Congenital Thrombotic Thrombocytopenic Purpura (TTP) in 2001 (Levy et al., PMID: 11586351). TTP is characterized by a deficiency of ADAMTS13 which may be congenital/familial due to inherited variants in the ADAMTS13 gene (also called Upshaw-Shulman syndrome) or acquired due to autoantibodies against ADAMTS13. ADAMTS13 cleaves ultra large von Willebrand Factor multimers into smaller multimers, rendering them less adhesive to platelets, preventing thrombosis. Genetic modifiers and environmental triggers are reported to play a role in the disease onset and severity. At least 175 ADAMTS13 variants, ranging from missense, in-frame indel to nonsense, frameshifts have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of case level data (12 points): Variants in this gene have been reported in at least 10 probands in 4 publications (PMIDs 11586351, 17003922, 19055667, 12393505). More evidence is available in the literature, but the maximum score for genetic evidence evidence (12 pts) has been reached. The mechanism for disease is loss of function (PMID: 11586351, 28416507, 27505881). Summary of experimental data (5 points): This gene-disease relationship is supported by animal models and in vitro functional assays (PMID: 12775718, 17003922). Many attempts at recapitulating the disease phenotype in mice have been made and was achieved with the injection of ultralarge VWF multimers as a trigger (PMID: 22529289). Rescue evidence in mouse is also available (PMID: 28254814, 22529289). In summary, ADAMTS13 is definitively associated with autosomal recessive Congenital Thrombotic Thrombocytopenic Purpura. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hemostasis/Thrombosis Gene Curation Expert Panel on March 25, 2020 (SOP Version 6).

congenital thrombotic thrombocytopenic purpuraSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010122

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Thrombotic thrombocytopenic purpura, hereditary (Schulman-Upshaw syndrome)AR

Manifestation: Hematologic; Neurologic; Renal

Intervention: Hematologic; Obstetric

Rationale: Medical management (eg, with administration of plasma; trials of recombinant ADAMTS13 have also had promising results) can be beneficial; Specific treatment in pregnancy may be indicated

Refs: 14443744; 651994; 7290149; 11530798; 11586351; 12181489; 12576319; 12637323; 19055667; 38692292

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ADAMTS13 variants in ClinVar

13 Conditions Cataloged

not providedTotal: 783

Upshaw-Schulman syndromeTotal: 398

not specifiedTotal: 171

Inborn genetic diseasesTotal: 167

ADAMTS13-related disorderTotal: 89

Thrombotic thrombocytopenic purpuraTotal: 11

Atypical hemolytic-uremic syndromeTotal: 3

ThrombusTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_139027.6. 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			22 clinvar	217 clinvar	2 clinvar	241
missense	11 clinvar	40 clinvar	427 clinvar	55 clinvar	1 clinvar	534
nonsense	13 clinvar	14 clinvar	1 clinvar			28
start loss	2 clinvar					2
frameshift	28 clinvar	19 clinvar	4 clinvar			51
splice donor/acceptor (+/-2bp)	2 clinvar	20 clinvar	5 clinvar			27
Total	56	93	459	272	3	883

Highest pathogenic variant AF is 0.0010945979

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 26 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_139027.6	RefSeq	NP_620596.2	29	MANE Select
ENST00000355699.7	Ensembl	ENSP00000347927.2	29	MANE Select
NM_139025.5	RefSeq	NP_620594.1	29	Standard
NM_139026.6	RefSeq	NP_620595.1	29	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Post-translational protein modification
Metabolism of proteins
O-glycosylation of TSR domain-containing proteins
O-linked glycosylation

Biological Process

proteolysis
cell-matrix adhesion
integrin-mediated signaling pathway
glycoprotein metabolic process
response to toxic substance

Molecular Function

metalloendopeptidase activity
integrin binding
calcium ion binding
protein binding
metallopeptidase activity

Cellular Component

extracellular space
endoplasmic reticulum lumen
cell surface
extracellular matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000371929
Coding exons: 29
Length: 45031
Individuals with no LoFs: 125676
Homozygous LoFs: 0
Heterozygous LoFs: 72
Defined: 125748
p: 0.000286

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.56	734	863	0.850	0.0000582	9105
Missense (PolyPhen)		176	235.34	0.74786		2683
Synonymous	0.864	337	358	0.942	0.0000241	2976
Loss of Function	3.70	35	67.9	0.515	0.00000333	740

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00033	0.00031	rare
Latino/Admixed American	0.00047	0.00046	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00056	0.00054	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00023	0.00023	rare
South Asian	0.00030	0.00029	rare
Other	0.00053	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Cleaves the vWF multimers in plasma into smaller forms thereby controlling vWF-mediated platelet thrombus formation. {ECO:0000269|PubMed:19880749}.;
Disease: DISEASE: Thrombotic thrombocytopenic purpura congenital (TTP) [MIM:274150]: A hematologic disease characterized by hemolytic anemia with fragmentation of erythrocytes, thrombocytopenia, diffuse and non-focal neurologic findings, decreased renal function and fever. recessive. {ECO:0000269|PubMed:11586351, ECO:0000269|PubMed:12181489, ECO:0000269|PubMed:12393505, ECO:0000269|PubMed:12614216, ECO:0000269|PubMed:12753286, ECO:0000269|PubMed:14512317, ECO:0000269|PubMed:14563640, ECO:0000269|PubMed:15009458, ECO:0000269|PubMed:15126318, ECO:0000269|PubMed:15327386, ECO:0000269|PubMed:16160007, ECO:0000269|PubMed:16449289, ECO:0000269|PubMed:16453338, ECO:0000269|PubMed:16796708, ECO:0000269|PubMed:16807643, ECO:0000269|PubMed:17003922, ECO:0000269|PubMed:18443791, ECO:0000269|PubMed:19055667, ECO:0000269|PubMed:19116307, ECO:0000269|PubMed:22075512}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.129

Intolerance Scores

LoFtool: 0.523
RVIS EVS: 0.62
RVIS percentile EVS: 83.42

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.150

Gene Damage Prediction

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