ST3GAL3

protein-coding

ST3 beta-galactoside alpha-2,3-sialyltransferase 3, the group of Sialyltransferases|MicroRNA protein coding host genes

Gene summary

The protein encoded by this gene is a type II membrane protein that catalyzes the transfer of sialic acid from CMP-sialic acid to galactose-containing substrates. The encoded protein is normally found in the Golgi apparatus but can be proteolytically processed to a soluble form. This protein is a member of glycosyltransferase family 29. Mutations in this gene have been associated with a form of autosomal recessive nonsymdromic cognitive disability as well as infantile epileptic encephalopathy. Multiple transcript variants encoding several different isoforms have been found for this gene. [provided by RefSeq, Jul 2017]

Previous symbols:

SIAT6
MRT12

MANE transcript

NM_006279.5

Inheritance

ClinVar variants

P:21U:149B:98

Top phenotype

Intellectual development disorder, autosomal recessive 12; Developmental and epileptic encephalopathy 15

gnomAD constraint

pLI —, LoF o/e 0.36

Max pathogenic AF

—

Genomic locus

chr1:43,705,824-43,931,165

External References & Databases

Ensembl (ENSG00000126091)

Transcript & Mutation Effects

hg38 • Region Span ~225.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex neurodevelopmental disorderMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: ClinGen

Variants in ST3GAL3 were first reported in a family with autosomal recessive complex neurodevelopmental disorder in 2011 (PMID: 21907012). Including the initial report, a total of four unique homozygous ST3GAL3 variants (three missense variants and one nonsense variant) in four families have been reported (PMID: 21907012, 23252400, 31584066). Clinical features observed in affected individuals include developmental delay, nonsyndromic intellectual disability, and epileptic encephalopathy (in two families). In one family, the ST3GAL3 variant segregated with disease in three additional family members (PMID: 23252400). ST3GAL3 encodes a sialyltransferase. Diminished enzyme activity and/or altered subcellular localization of the mutant protein were demonstrated by functional studies, supporting a loss-of-function disease mechanism (PMID: 21907012, 23252400, 31584066). This gene-disease relationship is further supported by functional alteration in patient cells, mouse models, and expression studies (PMID: 8027041, 22735313, 25846372, 30089820). In summary, there is moderate evidence to support this gene-disease association. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 6/3/2020.

developmental and epileptic encephalopathy, 15LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014003

Submitter: Ambry Genetics

intellectual developmental disorder, autosomal recessive 12STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012612

Submitter: G2P

intellectual developmental disorder, autosomal recessive 12STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012612

Submitter: PanelApp Australia

developmental and epileptic encephalopathy, 15STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014003

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Intellectual development disorder, autosomal recessive 12; Developmental and epileptic encephalopathy 15AR

Manifestation: 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: As with other conditions involving seizures, optimal seizure control is beneficial, and awareness of genetic causes may help with medication selection

Refs: 17120046; 21907012; 23252400

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ST3GAL3 variants in ClinVar

17 Conditions Cataloged

Early-infantile DEETotal: 260

Inborn genetic diseasesTotal: 77

not providedTotal: 72

Developmental and epileptic encephalopathyTotal: 54

not specifiedTotal: 44

Developmental and epileptic encephalopathy, 15Total: 21

ST3GAL3-related disorderTotal: 15

Intellectual disability, autosomal recessive 12Total: 15

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006279.5. 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			5 clinvar	97 clinvar		102
missense	3 clinvar	1 clinvar	139 clinvar	1 clinvar		144
nonsense	3 clinvar	2 clinvar	1 clinvar			6
start loss			1 clinvar			1
frameshift	3 clinvar		3 clinvar			6
splice donor/acceptor (+/-2bp)		9 clinvar				9
Total	9	12	149	98	0	268

Highest pathogenic variant AF is 0.000028045886

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 198 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006279.5	RefSeq	NP_006270.1	11	MANE Select
ENST00000347631.8	Ensembl	ENSP00000317192.6	11	MANE Select
NM_001270459.2	RefSeq	NP_001257388.1	11	Standard
NM_001270460.2	RefSeq	NP_001257389.1	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Other types of O-glycan biosynthesis - Homo sapiens (human)
Mannose type O-glycan biosynthesis - Homo sapiens (human)
Glycosphingolipid biosynthesis - lacto and neolacto series - Homo sapiens (human)
Glycosaminoglycan biosynthesis - keratan sulfate - Homo sapiens (human)
Glycosphingolipid biosynthesis - lactoseries

Biological Process

protein glycosylation
O-glycan processing
keratan sulfate biosynthetic process
sialylation

Molecular Function

beta-galactoside (CMP) alpha-2,3-sialyltransferase activity
N-acetyllactosaminide alpha-2,3-sialyltransferase activity
sialyltransferase activity

Cellular Component

Golgi membrane
extracellular region
integral component of membrane
Golgi cisterna membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000262915
Coding exons: 12
Length: 225337
Individuals with no LoFs: 125719
Homozygous LoFs: 0
Heterozygous LoFs: 29
Defined: 125748
p: 0.000115

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.50	188	255	0.736	0.0000172	2854
Missense (PolyPhen)		49	92.206	0.53142		1059
Synonymous	0.275	101	105	0.966	0.00000735	904
Loss of Function	3.00	9	25.3	0.356	0.00000144	301

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00027	0.00027	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000062	0.000062	rare
South Asian	0.00039	0.00039	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the formation of the NeuAc-alpha-2,3-Gal-beta- 1,4-GlcNAc-, NeuAc-alpha-2,3-Gal-beta-1,3-GlcNAc- and NeuAc-alpha- 2,3-Gal-beta-1,3-GalNAc- sequences found in terminal carbohydrate groups of glycoproteins and glycolipids. The highest activity is toward Gal-beta-1,3-GlcNAc and the lowest toward Gal-beta-1,3- GalNAc. {ECO:0000250|UniProtKB:P97325}.;
Disease: DISEASE: Mental retardation, autosomal recessive 12 (MRT12) [MIM:611090]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. {ECO:0000269|PubMed:21907012}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Epileptic encephalopathy, early infantile, 15 (EIEE15) [MIM:615006]: A form of epilepsy that manifests in the neonatal or the early infantile period as severely impaired cognitive and motor development, due to recurrent clinical seizures or prominent interictal epileptiform discharges. Patients develop infantile spasms, mainly of the flexor type, between 3 and 7 months of age, which are accompanied by hypsarrhythmia on EEG. Other features include poor eye contact, hypotonia, primitive reflexes, and irritability. Seizures evolve clinically to Lennox-Gastaut syndrome. {ECO:0000269|PubMed:23252400}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.106

Intolerance Scores

LoFtool: 0.589
RVIS EVS: -0.36
RVIS percentile EVS: 29.16

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.871

Gene Damage Prediction

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