ADAMTSL4

protein-coding

ADAMTS like 4, the group of ADAMTS like|MicroRNA protein coding host genes

Gene summary

This gene is a member of ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs)-like gene family and encodes a protein with seven thrombospondin type 1 repeats. The thrombospondin type 1 repeat domain is found in many proteins with diverse biological functions including cellular adhesion, angiogenesis, and patterning of the developing nervous system. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Sep 2014]

Previous symbols:

TSRC1

MANE transcript

NM_019032.6

Inheritance

AR, AD

ClinVar variants

P:188U:507B:451

Top phenotype

Ectopia lentis et pupillae; Ectopia lentis 2, isolated, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.86

Max pathogenic AF

—

Genomic locus

chr1:150,549,369-150,560,937

External References & Databases

Ensembl (ENSG00000143382)

Transcript & Mutation Effects

hg38 • Region Span ~11.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

ectopia lentis 2, isolated, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009152

Submitter: PanelApp Australia

ectopia lentis et pupillaeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009153

Submitter: Labcorp Genetics (formerly Invitae)

isolated ectopia lentisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015998

Submitter: Orphanet

ectopia lentis 2, isolated, autosomal recessiveDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009152

Submitter: G2P

ectopia lentis 2, isolated, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009152

Submitter: Ambry Genetics

ectopia lentis et pupillaeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009153

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Clinical Genomic Database (CGD)

Ectopia lentis et pupillae; Ectopia lentis 2, isolated, autosomal recessiveAR

Manifestation: Ophthalmologic

Intervention: Ophthalmologic; Pharmacogenomic

Rationale: Although management related to some manifestations may be made through clinical observations (eg, related to amblyopia), surveillance related to intraocular pressure monitoring may be beneficial to allow prompt interventions; preventive measures (eg, related to contact sports) may be beneficial; Agents that may contribute to glaucoma should be avoided

Refs: 2377351; 19200529; 20702823; 21051722; 22736615; 2338190

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ADAMTSL4 variants in ClinVar

12 Conditions Cataloged

not providedTotal: 1278

Inborn genetic diseasesTotal: 232

Ectopia lentis 2, isolated, autosomal recessiveTotal: 174

Ectopia lentis et pupillaeTotal: 125

ADAMTSL4-related disorderTotal: 94

not specifiedTotal: 76

Craniosynostosis with ectopia lentisTotal: 4

Isolated ectopia lentisTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_019032.6. 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			9 clinvar	406 clinvar	5 clinvar	420
missense	1 clinvar	4 clinvar	493 clinvar	36 clinvar	4 clinvar	538
nonsense	46 clinvar	13 clinvar				59
start loss		1 clinvar				1
frameshift	76 clinvar	24 clinvar	4 clinvar			104
splice donor/acceptor (+/-2bp)	2 clinvar	21 clinvar	1 clinvar			24
Total	125	63	507	442	9	1146

Highest pathogenic variant AF is 0.001757404

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_019032.6	RefSeq	NP_061905.2	17	MANE Select
ENST00000271643.9	Ensembl	ENSP00000271643.4	17	MANE Select
NM_001288607.2	RefSeq	NP_001275536.1	18	Standard
NM_001288608.2	RefSeq	NP_001275537.1	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

epithelial cell development
proteolysis
apoptotic process
extracellular matrix organization
positive regulation of apoptotic process

Molecular Function

protease binding
protein binding
peptidase activity

Cellular Component

cellular_component
interstitial matrix
endoplasmic reticulum lumen
collagen-containing extracellular matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000271643
Coding exons: 17
Length: 11530
Individuals with no LoFs: 125228
Homozygous LoFs: 1
Heterozygous LoFs: 519
Defined: 125748
p: 0.00207

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0800	666	672	0.991	0.0000450	6801
Missense (PolyPhen)		251	255.98	0.98055		2556
Synonymous	0.337	259	266	0.974	0.0000166	2357
Loss of Function	0.979	47	54.8	0.857	0.00000316	534

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0023	0.0022	notable
Latino/Admixed American	0.00091	0.00090	rare
Ashkenazi Jewish	0.00040	0.00040	rare
East Asian	0.00083	0.00082	rare
Finnish	0.0021	0.0021	notable
European (Non-Finnish)	0.0032	0.0031	notable
South Asian	0.00079	0.00078	rare
Other	0.0018	0.0018	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Positive regulation of apoptosis. May facilitate FBN1 microfibril biogenesis. {ECO:0000269|PubMed:16364318, ECO:0000269|PubMed:21989719}.;
Disease: DISEASE: Ectopia lentis 2, isolated, autosomal recessive (ECTOL2) [MIM:225100]: An ocular abnormality characterized by partial or complete displacement of the lens from its space resulting from defective zonule formation. {ECO:0000269|PubMed:19200529}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Ectopia lentis et pupillae (ECTOLP) [MIM:225200]: An ocular abnormality characterized by displacement of the lenses and the pupils, associated with other ocular anomalies, but without systemic manifestations. The condition is usually bilateral, with the lenses and pupils displaced in opposite directions. Additional signs include enlarged corneal diameter, increased corneal astigmatism, increased anterior chamber depth, thinning and flattening of the iris with loss of crypts, angle malformation caused by enlarged iris processes, persistent pupillary membrane, loss of zonular fibers, tilted disk, and increased axial length. Secondary manifestations include refractive errors, glaucoma, early cataract development, and retinal detachment. Membrane formation on the posterior aspect of the iris has been observed both in histologic sections and on ultrasound biomicroscopy. {ECO:0000269|PubMed:20702823}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0987

Intolerance Scores

LoFtool: 0.989
RVIS EVS: 0
RVIS percentile EVS: 53.51

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.853

Gene Damage Prediction

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