STT3A
protein-codingSTT3 oligosaccharyltransferase complex catalytic subunit A, the group of Oligosaccharyltransferase complex subunits|STT3 oligosaccharyltransferase catalytic subunits
Gene summary
The protein encoded by this gene is a catalytic subunit of the N-oligosaccharyltransferase (OST) complex, which functions in the endoplasmic reticulum to transfer glycan chains to asparagine residues of target proteins. A separate complex containing a similar catalytic subunit with an overlapping function also exists. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2015]
- ITM1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~33.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014270
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0014270
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0859223
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0859223
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0014270
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0014270
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014270
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0859223
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0014270
Submitter: ClinGen
STT3A was first reported in relation to autosomal recessive STT3A-congenital disorder of glycosylation (CDG type 1w) in 2013 (Shrimal et al., PMID 23842455). Two variants (missense) that have been reported in 3 probands in 3 publications (PMIDs 23842455, 28424003, 30701557) are included in this curation. Patients have a range of symptoms, including developmental delay, intellectual disability, failure to thrive, hypotonia and seizures. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in STT3A have been reported in individuals with the following disease entities: autosomal dominant congenital disorder of glycosylation, type Iw (MIM: 619714) and autosomal recessive congenital disorder of glycosylation, type Iw (MIM: 615596). Per criteria outlined by the ClinGen Lumping and Splitting guidelines, the curation for autosomal dominant congenital disorder of glycosylation, type 1w has been curated separately. This gene-disease relationship is supported by in vitro and in vivo assays showing a defect in N-linked glycosylation (PMIDs 23842455, 30701557, 19167329) as well as a zebrafish model (PMID 39891251). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.This classification was approved by the ClinGen Congenital Disorders of Glycosylation GCEP on the meeting date April 16, 2025 (SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0859223
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0859223
Submitter: ClinGen
STT3A was first reported in relation to autosomal dominant congenital disorder of glycosylation, type Iw in 2021 (Wilson et al., PMID 34653363). At least nine variants (missense) that have been reported in 11 probands in 3 publications (PMIDs 34653363, 39891251, 39435313) are included in this curation. Patients have a range of symptoms, including developmental delay, intellectual disability, skeletal anomalies, short stature, macrocephaly, dysmorphic features, and muscle cramps. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in STT3A have been reported in individuals with the following disease entities: autosomal dominant congenital disorder of glycosylation, type Iw (MIM: 619714) and autosomal recessive congenital disorder of glycosylation, type Iw (MIM: 615596). Per criteria outlined by the ClinGen Lumping and Splitting guidelines, the curation for autosomal recessive congenital disorder of glycosylation, type 1w has been curated separately. This gene-disease relationship is supported by in vitro and in vivo assays showing a defect in N-linked glycosylation (PMIDs 34653363, 19167329) as well as a zebrafish model (PMID 39891251). In summary, there is definitive evidence to support the relationship between STT3A and autosomal dominant congenital disorder of glycosylation, type Iw. 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 Congenital Disorders of Glycosylation GCEP on the meeting date June 5, 2025 (SOP Version 11).
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Craniofacial; Musculoskeletal; Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
Comments: Hepatic-metabolized agents should be avoided
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to STT3A variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_152713.5. 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 | 4 | 37 | 1 | 42 | ||
| missense | 7 | 120 | 127 | |||
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 14 | 14 | ||||
| Total | 0 | 7 | 140 | 37 | 1 | 185 |
Highest pathogenic variant AF is 0.000024215331
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_689926.1 | 17 | MANE Select | |
| Ensembl | ENSP00000376472.3 | 17 | MANE Select | |
| RefSeq | NP_001265432.1 | 17 | Standard | |
| RefSeq | NP_001265433.1 | 14 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Protein processing in endoplasmic reticulum - Homo sapiens (human)
- N-Glycan biosynthesis - Homo sapiens (human)
- Post-translational protein modification
- Metabolism of proteins
- Asparagine N-linked glycosylation
Biological Process
- protein N-linked glycosylation via asparagine
- co-translational protein modification
Molecular Function
- dolichyl-diphosphooligosaccharide-protein glycotransferase activity
- protein binding
- metal ion binding
Cellular Component
- endoplasmic reticulum membrane
- oligosaccharyltransferase complex
- membrane
- integral component of membrane
- oligosaccharyltransferase III complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000392708
- Coding exons
- 17
- Length
- 33504
- Individuals with no LoFs
- 125725
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 21
- Defined
- 125746
- p
- 0.0000835
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.62 | 205 | 412 | 0.498 | 0.0000229 | 4610 |
| Missense (PolyPhen) | 45 | 173.6 | 0.25921 | 2021 | ||
| Synonymous | 1.43 | 122 | 144 | 0.849 | 0.00000736 | 1385 |
| Loss of Function | 4.18 | 13 | 42.3 | 0.307 | 0.00000257 | 440 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.00012 | 0.00012 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00022 | 0.00022 | rare |
| Finnish | 0.00014 | 0.00014 | rare |
| European (Non-Finnish) | 0.000062 | 0.000062 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Catalytic subunit of the oligosaccharyl transferase (OST) complex that catalyzes the initial transfer of a defined glycan (Glc(3)Man(9)GlcNAc(2) in eukaryotes) from the lipid carrier dolichol-pyrophosphate to an asparagine residue within an Asn-X-Ser/Thr consensus motif in nascent polypeptide chains, the first step in protein N-glycosylation. N-glycosylation occurs cotranslationally and the complex associates with the Sec61 complex at the channel-forming translocon complex that mediates protein translocation across the endoplasmic reticulum (ER). All subunits are required for a maximal enzyme activity. This subunit contains the active site and the acceptor peptide and donor lipid- linked oligosaccharide (LLO) binding pockets (By similarity). STT3A is present in the majority of OST complexes and mediates cotranslational N-glycosylation of most sites on target proteins, while STT3B-containing complexes are required for efficient post- translational glycosylation and mediate glycosylation of sites that have been skipped by STT3A (PubMed:19167329). {ECO:0000250|UniProtKB:P39007, ECO:0000269|PubMed:19167329}.;
- Disease
- DISEASE: Congenital disorder of glycosylation 1W (CDG1W) [MIM:615596]: A form of congenital disorder of glycosylation, a multisystem disorder caused by a defect in glycoprotein biosynthesis and characterized by under-glycosylated serum glycoproteins. Congenital disorders of glycosylation result in a wide variety of clinical features, such as defects in the nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. The broad spectrum of features reflects the critical role of N-glycoproteins during embryonic development, differentiation, and maintenance of cell functions. {ECO:0000269|PubMed:23842455}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.276
- RVIS EVS
- -0.65
- RVIS percentile EVS
- 16.36
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- H
- Indispensability pred.
- E
- Indispensability score
- 0.967
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |