GALNT3
protein-codingpolypeptide N-acetylgalactosaminyltransferase 3, the group of Polypeptide N-acetylgalactosaminyltransferases
Gene summary
This gene encodes UDP-GalNAc transferase 3, a member of the GalNAc-transferases family. This family transfers an N-acetyl galactosamine to the hydroxyl group of a serine or threonine residue in the first step of O-linked oligosaccharide biosynthesis. Individual GalNAc-transferases have distinct activities and initiation of O-glycosylation is regulated by a repertoire of GalNAc-transferases. The protein encoded by this gene is highly homologous to other family members, however the enzymes have different substrate specificities. [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 ~98.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0100252
Submitter: Natera
Inheritance Pattern: AR
Disease ID:MONDO:0008897
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0100252
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0100252
Submitter: ClinGen
GALNT3 was first reported in relation to autosomal recessive Tumoral calcinosis, hyperphosphatemic, familial, 1 [HFTC] (MONDO:100252) in 2004 (N Topaz O et al., 2004, PMID:15133511). HFTC is a rare autosomal recessive metabolic disorder characterized by the progressive deposition of basic calcium phosphate crystals in periarticular spaces, soft tissues, and sometimes bone. The disease can be caused by recessive mutations in at least two different genes: GalNAc transferase 3 (GALNT3), encoding a glycosyltransferase that initiates mucin-type O-glycosylation, and fibroblast growth factor 23 (FGF23), which encodes a regulator of phosphate circulating levels. The biochemical hallmark of tumoral calcinosis is hyperphosphatemia caused by increased renal absorption of phosphate due to loss-of-function mutations in the FGF23 (OMIM:605380) or GALNT3 gene (Kato et al., 2006, PMID:16638743). The GALNT3 gene provides instructions for making a protein called ppGalNacT3, which is found in many types of cells. This protein plays a leading role in regulating phosphate levels within the body (phosphate homeostasis). Among its many functions, phosphate plays a critical role in the formation and growth of bones in childhood and helps maintain bone strength in adults. Phosphate levels are controlled by the kidneys. The kidneys normally rid the body of excess phosphate by excreting it in urine, and they reabsorb this mineral into the bloodstream when more is needed. More than 220 unique variants (e.g., synonymous, missense, in-frame indel, nonsense, frameshift) have been reported in humans by ClinVar. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Seven variants (1 nonsense, 1 missense, 2 splice donors, 1 splice acceptor, 1 frame-shift and 1 intron) that have been reported in approximately 6 probands in 3 publications (Topaz O et al., 2004, PMID:15133511; Ichikawa S et al., 2005, PMID: 15687324; and Ichikawa S et al. 2010; PMID:20358599), are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is also supported by protein interaction, and animal models studies (Kato et al., 2006, PMID: 16638743; Ichikawa et al., 2009, PMID: 19213845; Ichikawa et al., 2014, PMID: 25051439). In summary, there is definitive evidence to support the relationship between GALNT3 and Tumoral calcinosis, hyperphosphatemic, familial, 1. 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 January 3, 2024 (SOP Version 10).
Inheritance Pattern: AR
Disease ID:MONDO:0008897
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0100252
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0100252
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Dermatologic; Musculoskeletal; Renal
Intervention: Renal
Rationale: Individuals may manifest with sequelae (ie, increased calcium phosphate deposition) of hyperphosphatemia due to increased renal phosphate absorption, and phosphate reduction (eg, with dietary means and phosphate-binding agents) can be beneficial, though families for whom treatment was not effective have been reported
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to GALNT3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_004482.4. 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 | 2 | 140 | 142 | |||
| missense | 5 | 13 | 178 | 3 | 3 | 202 |
| nonsense | 13 | 4 | 17 | |||
| start loss | 0 | |||||
| frameshift | 14 | 5 | 19 | |||
| splice donor/acceptor (+/-2bp) | 5 | 11 | 1 | 17 | ||
| Total | 37 | 33 | 181 | 143 | 3 | 397 |
Highest pathogenic variant AF is 0.000053282514
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_004473.2 | 10 | MANE Select | |
| Ensembl | ENSP00000376465.3 | 10 | MANE Select | |
| Ensembl | ENSP00000386955.1 | 8 | Standard | |
| Ensembl | ENSP00000386955.1 | 8 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Mucin type O-glycan biosynthesis - Homo sapiens (human)
- FGFR3c ligand binding and activation
- Signaling by FGFR3
- Signal Transduction
- Signaling by FGFR
Biological Process
- carbohydrate metabolic process
- fibroblast growth factor receptor signaling pathway
- O-glycan processing
- protein O-linked glycosylation via serine
- protein O-linked glycosylation via threonine
Molecular Function
- polypeptide N-acetylgalactosaminyltransferase activity
- calcium ion binding
- manganese ion binding
- carbohydrate binding
Cellular Component
- Golgi membrane
- Golgi apparatus
- membrane
- integral component of membrane
- Golgi cisterna membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000392701
- Coding exons
- 10
- Length
- 47092
- Individuals with no LoFs
- 125648
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 98
- Defined
- 125746
- p
- 0.000390
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.386 | 317 | 337 | 0.941 | 0.0000173 | 4190 |
| Missense (PolyPhen) | 138 | 160.69 | 0.85879 | 1927 | ||
| Synonymous | 0.491 | 106 | 113 | 0.941 | 0.00000586 | 1161 |
| Loss of Function | 2.16 | 18 | 30.9 | 0.582 | 0.00000163 | 393 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.0020 | 0.0019 | notable |
| Latino/Admixed American | 0.00026 | 0.00026 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.00049 | 0.00049 | rare |
| Finnish | 0.00011 | 0.000092 | rare |
| European (Non-Finnish) | 0.00034 | 0.00034 | rare |
| South Asian | 0.00020 | 0.00020 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Catalyzes the initial reaction in O-linked oligosaccharide biosynthesis, the transfer of an N-acetyl-D- galactosamine residue to a serine or threonine residue on the protein receptor. Has activity toward HIV envelope glycoprotein gp120, EA2, Muc2 and Muc5. Probably glycosylates fibronectin in vivo. Glycosylates FGF23. Plays a central role in phosphate homeostasis. {ECO:0000269|PubMed:16638743, ECO:0000269|PubMed:9295285}.;
- Disease
- DISEASE: Tumoral calcinosis, hyperphosphatemic, familial, 1 (HFTC1) [MIM:211900]: A form of hyperphosphatemic tumoral calcinosis, a rare autosomal recessive metabolic disorder that manifests with hyperphosphatemia and massive calcium deposits in the skin and subcutaneous tissues. Some patients have recurrent, transient, painful swellings of the long bones associated with the radiographic findings of periosteal reaction and cortical hyperostosis and absence of skin involvement. {ECO:0000269|PubMed:15133511, ECO:0000269|PubMed:15599692}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.676
- RVIS EVS
- -0.38
- RVIS percentile EVS
- 28.11
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.189
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |