EXT1
protein-codingexostosin glycosyltransferase 1, the group of Exostosin glycosyltransferase family
Gene summary
This gene encodes an endoplasmic reticulum-resident type II transmembrane glycosyltransferase involved in the chain elongation step of heparan sulfate biosynthesis. Mutations in this gene cause the type I form of multiple exostoses. [provided by RefSeq, Jul 2008]
- LGCR
- LGS
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~317.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0005508
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007585
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0007585
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0007585
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0007585
Submitter: ClinGen
There has been sufficient amount of evidence published associating the EXT1 gene with Hereditary Multiple Exostoses (HME) since the gene-disease relationship was first proposed by Ahn et al. (1995). Plenty of case level studies have been performed with HME patients that have variants in the EXT1 gene. EXT2 also cause hereditary multiple exostoses and a working model for the formation of exostoses has been proposed to link the heparan sulfate biosynthesis function of EXT1. Multiple mouse models have been established to show the development of osteochondromas and exostoses with EXT1 deficiency. All of these evidence suggest a definitive relationship between the EXT1 gene and Hereditary Multiple Exostoses (HME).
Inheritance Pattern: AD
Disease ID:MONDO:0008977
Submitter: Genomics England PanelApp
Clinical Genomic Database (CGD)
Manifestation: Musculoskeletal; Oncologic
Intervention: Oncologic
Rationale: In Exostoses, multiple, type 1, though data regarding the efficacy of surveillance are lacking, individuals are at risk for the (relatively infrequent) development of malignant change of exostoses, and awareness may allow early detection and management; In Chondrosarcoma, individuals may be at risk of chondrosarcoma, and awareness may allow early diagnosis and management
Comments: Though onset of malignancy is typically described in adulthood, some individuals have been affected at an earlier age; Germline variants have also been implicated in chondrosarcoma
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to EXT1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000127.3. 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 | 4 | 157 | 8 | 169 | ||
| missense | 18 | 35 | 362 | 30 | 5 | 450 |
| nonsense | 128 | 24 | 4 | 156 | ||
| start loss | 2 | 1 | 3 | |||
| frameshift | 245 | 42 | 2 | 289 | ||
| splice donor/acceptor (+/-2bp) | 65 | 11 | 4 | 80 | ||
| Total | 458 | 113 | 376 | 187 | 13 | 1147 |
Highest pathogenic variant AF is 0.000006571079
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000118.2 | 11 | MANE Select | |
| Ensembl | ENSP00000367446.3 | 11 | MANE Select | |
| Ensembl | ENSP00000400372.1 | 5 | Standard | |
| Ensembl | ENSP00000407299.1 | 2 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Glycosaminoglycan biosynthesis - heparan sulfate / heparin - Homo sapiens (human)
- Endoderm Differentiation
- Mesodermal Commitment Pathway
- Olfactory bulb development and olfactory learning
- Metabolism of carbohydrates
Biological Process
- skeletal system development
- ossification
- glycosaminoglycan biosynthetic process
- protein glycosylation
- signal transduction
Molecular Function
- acetylglucosaminyltransferase activity
- glucuronosyltransferase activity
- transferase activity, transferring glycosyl groups
- heparan sulfate N-acetylglucosaminyltransferase activity
- protein homodimerization activity
Cellular Component
- Golgi membrane
- endoplasmic reticulum
- endoplasmic reticulum membrane
- Golgi apparatus
- integral component of membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000378204
- Coding exons
- 11
- Length
- 317364
- Individuals with no LoFs
- 125741
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 7
- Defined
- 125748
- p
- 0.0000278
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.67 | 317 | 412 | 0.769 | 0.0000223 | 4940 |
| Missense (PolyPhen) | 90 | 171.94 | 0.52344 | 2147 | ||
| Synonymous | -0.729 | 171 | 159 | 1.07 | 0.00000924 | 1399 |
| Loss of Function | 4.86 | 4 | 35.0 | 0.114 | 0.00000161 | 420 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0.00010 | 0.000099 | rare |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0.000047 | 0.000046 | rare |
| European (Non-Finnish) | 0.000026 | 0.000026 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Glycosyltransferase required for the biosynthesis of heparan-sulfate. The EXT1/EXT2 complex possesses substantially higher glycosyltransferase activity than EXT1 or EXT2 alone. Appears to be a tumor suppressor. Required for the exosomal release of SDCBP, CD63 and syndecan (PubMed:22660413). {ECO:0000269|PubMed:11518722, ECO:0000269|PubMed:22660413}.;
- Disease
- DISEASE: Tricho-rhino-phalangeal syndrome 2 (TRPS2) [MIM:150230]: A syndrome that combines the clinical features of tricho-rhino- phalangeal syndrome type 1 and multiple exostoses type 1. Affected individuals manifest multiple dysmorphic facial features including large, laterally protruding ears, a bulbous nose, an elongated upper lip, as well as sparse scalp hair, winged scapulae, multiple cartilaginous exostoses, redundant skin, and mental retardation. Note=The gene represented in this entry is involved in disease pathogenesis. A chromosomal aberration resulting in the loss of functional copies of TRPS1 and EXT1 has been found in TRPS2 patients.; DISEASE: Chondrosarcoma (CHDSA) [MIM:215300]: A malignant neoplasm derived from cartilage cells. Chondrosarcomas range from slow- growing non-metastasizing lesions to highly aggressive metastasizing sarcomas. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.268
Intolerance Scores
- LoFtool
- 0.00765
- RVIS EVS
- -1.13
- RVIS percentile EVS
- 6.43
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.819
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |