ADAMTSL2

protein-coding

ADAMTS like 2, the group of ADAMTS like

Gene summary

This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) and ADAMTS-like 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 protein encoded by this gene lacks the protease domain, and is therefore of a member of the the ADAMTS-like protein subfamily. It is a secreted glycoprotein that binds the cell surface and extracellular matrix; it also interacts with latent transforming growth factor beta binding protein 1. Mutations in this gene have been associated with geleophysic dysplasia. [provided by RefSeq, Feb 2009]

MANE transcript

NM_014694.4

Inheritance

AR, AD

ClinVar variants

P:26U:174B:61

Top phenotype

Geleophysic dysplasia 1

gnomAD constraint

pLI —, LoF o/e 0.41

Max pathogenic AF

—

Genomic locus

chr9:133,532,164-133,575,519

External References & Databases

Ensembl (ENSG00000197859)

Transcript & Mutation Effects

hg38 • Region Span ~43.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

geleophysic dysplasia 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009269

Submitter: Ambry Genetics

geleophysic dysplasia 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009269

Submitter: PanelApp Australia

Ehlers-Danlos syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0020066

Submitter: Ambry Genetics

geleophysic dysplasia 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009269

Submitter: G2P

geleophysic dysplasia 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009269

Submitter: Labcorp Genetics (formerly Invitae)

Ehlers-Danlos syndrome, dermatosparaxis typeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0009161

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Geleophysic dysplasia 1AR

Manifestation: Biochemical; Cardiovascular; Craniofacial; Gastrointestinal; Musculoskeletal

Intervention: Cardiovascular

Rationale: The disorder may frequently be clinically recognizable, but individuals can have cardiovascular manifestations such as progressive cardiac valve thickening necessitating surgical interventions very early in childhood, and early diagnosis may be beneficial to allow early treatment

Refs: 18677313; 21415077; 21683322; 20301776

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ADAMTSL2 variants in ClinVar

8 Conditions Cataloged

Geleophysic dysplasia 1Total: 118

Inborn genetic diseasesTotal: 95

not providedTotal: 69

not specifiedTotal: 63

ADAMTSL2-related disorderTotal: 31

Lethal short-limb skeletal dysplasia, Al Gazali typeTotal: 14

Abnormal facial shapeTotal: 1

Geleophysic dysplasiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014694.4. 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	50 clinvar		76
missense	4 clinvar	10 clinvar	144 clinvar	11 clinvar		169
nonsense	1 clinvar	7 clinvar				8
start loss						0
frameshift		2 clinvar				2
splice donor/acceptor (+/-2bp)	1 clinvar	1 clinvar	4 clinvar			6
Total	6	20	174	61	0	261

Highest pathogenic variant AF is 0.000014872819

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 44 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014694.4	RefSeq	NP_055509.2	18	MANE Select
ENST00000651351.2	Ensembl	ENSP00000498961.2	18	MANE Select
NM_001145320.2	RefSeq	NP_001138792.1	18	Standard
ENST00000354484.8	Ensembl	ENSP00000346478.4	18	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
extracellular matrix organization
negative regulation of transforming growth factor beta receptor signaling pathway
lobar bronchus epithelium development

Molecular Function

protein binding
peptidase activity
microfibril binding

Cellular Component

extracellular matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000354484
Coding exons: 18
Length: 43356
Individuals with no LoFs: 125739
Homozygous LoFs: 0
Heterozygous LoFs: 8
Defined: 125747
p: 0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.25	185	239	0.773	0.0000167	6245
Missense (PolyPhen)		49	93.051	0.52659		2292
Synonymous	-1.83	136	111	1.22	0.00000919	1861
Loss of Function	2.43	8	19.6	0.408	0.00000102	519

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.000027	0.000026	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Disease: DISEASE: Geleophysic dysplasia 1 (GPHYSD1) [MIM:231050]: An autosomal recessive disorder characterized by severe short stature, short hands and feet, joint limitations, and skin thickening. Radiologic features include delayed bone age, cone- shaped epiphyses, shortened long tubular bones, and ovoid vertebral bodies. Affected individuals have characteristic facial features including a 'happy' face with full cheeks, shortened nose, hypertelorism, long and flat philtrum, and thin upper lip. Other distinctive features include progressive cardiac valvular thickening often leading to an early death, toe walking, tracheal stenosis, respiratory insufficiency, and lysosomal-like storage vacuoles in various tissues. {ECO:0000269|PubMed:18677313, ECO:0000269|PubMed:21415077}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.115

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.247

Gene Damage Prediction

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