ALG12
protein-codingALG12 alpha-1,6-mannosyltransferase, the group of Dolichyl D-mannosyl phosphate dependent mannosyltransferases
Gene summary
This gene encodes a member of the glycosyltransferase 22 family. The encoded protein catalyzes the addition of the eighth mannose residue in an alpha-1,6 linkage onto the dolichol-PP-oligosaccharide precursor (dolichol-PP-Man(7)GlcNAc(2)) required for protein glycosylation. Mutations in this gene have been associated with congenital disorder of glycosylation type Ig (CDG-Ig)characterized by abnormal N-glycosylation. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~18.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0011783
Submitter: ClinGen
*ALG12* was first reported in relation to autosomal recessive *ALG12*-congenital disorder of glycosylation (also known as congenital disorder of glycosylation type Ig) in 2002 (Chantret et. al., PMID 11983712). Common phenotypes include intellectual disability, hypotonia, dysmorphic features, coagulation abnormalities and genitourinary abnormalities. Twenty-two unique variants (missense, nonsense, frameshift and an in-frame indel) that have been reported in 14 individuals across 11 publications (PMIDs: 11983712, 12093361, 12217961, 15639192, 16435218, 17506107, 25019053, 31529350, 34092405, 34467644, 34602961) are included in this curation. Several variants were evaluated but not scored due to high allele frequency in gnomAD (PMID: 31743061), discordant phenotypes (PMIDs: 31481313, 32530140), or lack of supporting biochemical evidence (PMID: 33461977). The mechanism of pathogenicity is known to be loss-of-function. This gene-disease association is also supported by biochemical evidence. The protein encoded by *ALG12* is involved in the N-linked glycoprotein synthesis pathway; loss-of-function of different proteins in this pathway have been associated with intellectual disability (PMID: 23798010). In summary, there is definitive evidence to support the relationship between *ALG12* and autosomal recessive *ALG12*-congenital disorder of glycosylation. 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 Intellectual Disability and Autism Gene Curation Expert Panel on February 15, 2023 (SOP Version 9).
Inheritance Pattern: AR
Disease ID:MONDO:0011783
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0011783
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0011783
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0011783
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0011783
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Biochemical; Cardiovascular; Craniofacial; Genitourinary; Hematologic; Musculoskeletal; Neurologic
Intervention: Allergy/Immunology/Infectious; Cardiovascular; Hematologic
Rationale: As the condition can include immunodeficiency and frequent infections, prophylaxis and early and aggressive treatment of infections may be beneficial; Awareness of coagulopathies may be beneficial in terms of medical management, especially in situations such as surgery; Individuals have been described with congenital heart anomalies, and awareness may enable early diagnosis and management
Comments: Hepatic-metabolized agents should be avoided
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ALG12 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_024105.4. 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 | 4 | 185 | 1 | 190 | ||
| missense | 1 | 10 | 201 | 15 | 2 | 229 |
| nonsense | 9 | 1 | 10 | |||
| start loss | 0 | |||||
| frameshift | 10 | 7 | 1 | 18 | ||
| splice donor/acceptor (+/-2bp) | 10 | 2 | 12 | |||
| Total | 20 | 28 | 208 | 200 | 3 | 459 |
Highest pathogenic variant AF is 0.00012332367
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_077010.1 | 9 | MANE Select | |
| Ensembl | ENSP00000333813.5 | 9 | MANE Select | |
| Ensembl | ENSP00000420630.1 | 4 | Standard | |
| Ensembl | ENSP00000417387.1 | 5 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- N-Glycan biosynthesis - Homo sapiens (human)
- Post-translational protein modification
- Metabolism of proteins
- Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein
- Asparagine N-linked glycosylation
Biological Process
- protein folding
- protein N-linked glycosylation
- dolichol-linked oligosaccharide biosynthetic process
- mannosylation
Molecular Function
- mannosyltransferase activity
- dolichyl-pyrophosphate Man7GlcNAc2 alpha-1,6-mannosyltransferase activity
- dol-P-Man:Man(7)GlcNAc(2)-PP-Dol alpha-1,6-mannosyltransferase activity
Cellular Component
- endoplasmic reticulum
- endoplasmic reticulum lumen
- endoplasmic reticulum membrane
- membrane
- integral component of membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000330817
- Coding exons
- 9
- Length
- 18230
- Individuals with no LoFs
- 125677
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 70
- Defined
- 125747
- p
- 0.000278
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.193 | 295 | 286 | 1.03 | 0.0000199 | 3077 |
| Missense (PolyPhen) | 107 | 107.61 | 0.99431 | 1246 | ||
| Synonymous | -1.87 | 166 | 138 | 1.20 | 0.0000107 | 1094 |
| Loss of Function | 1.45 | 14 | 21.2 | 0.661 | 0.00000102 | 234 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00025 | 0.00025 | rare |
| Latino/Admixed American | 0.00064 | 0.00064 | rare |
| Ashkenazi Jewish | 0.00020 | 0.00020 | rare |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0.00028 | 0.00028 | rare |
| European (Non-Finnish) | 0.00032 | 0.00027 | rare |
| South Asian | 0.000098 | 0.000098 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Adds the eighth mannose residue in an alpha-1,6 linkage onto the dolichol-PP-oligosaccharide precursor (dolichol-PP- Man(7)GlcNAc(2)) required for protein glycosylation.;
Recessive Scores
- pRec
- 0.141
Intolerance Scores
- LoFtool
- 0.420
- RVIS EVS
- -0.64
- RVIS percentile EVS
- 16.68
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.352
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |