ST3GAL5

protein-coding

ST3 beta-galactoside alpha-2,3-sialyltransferase 5, the group of Sialyltransferases

Gene summary

Ganglioside GM3 is known to participate in the induction of cell differentiation, modulation of cell proliferation, maintenance of fibroblast morphology, signal transduction, and integrin-mediated cell adhesion. The protein encoded by this gene is a type II membrane protein which catalyzes the formation of GM3 using lactosylceramide as the substrate. The encoded protein is a member of glycosyltransferase family 29 and may be localized to the Golgi apparatus. Mutation in this gene has been associated with Amish infantile epilepsy syndrome. Transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Previous symbols:

SIAT9

MANE transcript

NM_003896.4

Inheritance

ClinVar variants

P:56U:161B:133

Top phenotype

Salt and pepper developmental regression syndrome (Ganglioside GM3 synthase deficiency)

gnomAD constraint

pLI —, LoF o/e 0.42

Max pathogenic AF

—

Genomic locus

chr2:85,837,120-85,905,199

External References & Databases

Ensembl (ENSG00000115525)

Transcript & Mutation Effects

hg38 • Region Span ~68.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

GM3 synthase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0018274

Submitter: PanelApp Australia

GM3 synthase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0018274

Submitter: Labcorp Genetics (formerly Invitae)

GM3 synthase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018274

Submitter: G2P

GM3 synthase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018274

Submitter: ClinGen

Biallellic likely pathogenic/pathogenic variants in the *ST3GAL5* gene were first reported in individuals with infantile-onset symptomatic epilepsy associated with developmental stagnation and blindness in 2004 (Simpson et al., PMID 15502825). Autosomal recessive “Salt and pepper developmental regression syndrome”, or GM3 synthase deficiency, was initially described in 1983 and is characterized by severe intellectual disability, microcephaly, midface hypoplasia, prominent lower face, scoliosis, choreoathetosis and spasticity. Phenotypic variability has been reported concerning mainly the occurrence of seizures and the presence of abnormal skin pigmentation (scattered hyper- and hypo- pigmented macules) at early stages. The most common underlying mechanism involves biparentally inherited loss-of-function *ST3GAL5* variants leading to GM3 synthase deficiency. One recurrent nonsense variant was detected in 14 probands (PMIDs: 15502825, 22990144, 25131622, 30185102) and additional variants include one frameshift alteration (PMID: 34385424) and four missense variants in 8 probands (PMIDs: 24026681, 27232954, 30576498). Functional studies indicated the absence of GM3 and derivatives in plasma samples (PMIDs: 15502825, 22990144, 24026681, 27232954) and fibroblasts (PMID: 24026681) from patients; as well as the complete loss of enzyme activity in transfected HEK-293T cells of expression plasmids carrying wild type and mutated *ST3GAL5* cDNAs (PMID: 30576498). In summary, *ST3GAL5* is definitively associated with the autosomal recessive GM3 synthase deficiency as it has been repeatedly demonstrated in both research and clinical diagnostic settings and has been upheld over time. Approved by the ClinGen Epilepsy Gene Curation Expert Panel on April 5, 2022 (SOP version 8).

Clinical Genomic Database (CGD)

Salt and pepper developmental regression syndrome (Ganglioside GM3 synthase deficiency)AR

Manifestation: Dermatologic; Neurologic; Ophthalmologic

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: Treatment with ubiquinone has been described, but the overall efficacy is unclear

Refs: 4213132; 15502825; 22990144; 23436467

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ST3GAL5 variants in ClinVar

6 Conditions Cataloged

GM3 synthase deficiencyTotal: 420

not providedTotal: 59

Inborn genetic diseasesTotal: 46

not specifiedTotal: 27

ST3GAL5-related disorderTotal: 9

Intellectual disabilityTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003896.4. 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 clinvar	119 clinvar		123
missense	1 clinvar	8 clinvar	155 clinvar	14 clinvar		178
nonsense	12 clinvar	2 clinvar				14
start loss						0
frameshift	16 clinvar	7 clinvar	2 clinvar			25
splice donor/acceptor (+/-2bp)	4 clinvar	6 clinvar				10
Total	33	23	161	133	0	350

Highest pathogenic variant AF is 0.00006133647

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 101 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003896.4	RefSeq	NP_003887.3	7	MANE Select
ENST00000638572.2	Ensembl	ENSP00000491316.1	7	MANE Select
NM_001042437.2	RefSeq	NP_001035902.1	7	Standard
NM_001354223.2	RefSeq	NP_001341152.1	4	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
st3gal5	Danio rerio	Structure: midbrain Quality: increased occurrence abnormal

Gene / Model

Organism

Observed Phenotype

st3gal5

Danio rerio

Structure: midbrain

Quality: increased occurrence

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Glycosphingolipid biosynthesis - ganglio series - Homo sapiens (human)
Ganglio Sphingolipid Metabolism
Post-translational protein modification
Metabolism of proteins
Glycosphingolipid biosynthesis - ganglioseries

Biological Process

ganglioside biosynthetic process
carbohydrate metabolic process
protein glycosylation
glycosphingolipid biosynthetic process
sialylation

Molecular Function

beta-galactoside (CMP) alpha-2,3-sialyltransferase activity
neolactotetraosylceramide alpha-2,3-sialyltransferase activity
sialyltransferase activity
lactosylceramide alpha-2,3-sialyltransferase activity

Cellular Component

Golgi membrane
integral component of plasma membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000377332
Coding exons: 7
Length: 49871
Individuals with no LoFs: 125698
Homozygous LoFs: 0
Heterozygous LoFs: 50
Defined: 125748
p: 0.000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.05	168	211	0.797	0.0000117	2735
Missense (PolyPhen)		48	77.081	0.62272		960
Synonymous	1.23	65	78.9	0.824	0.00000462	785
Loss of Function	2.35	8	19.1	0.419	0.00000109	245

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00033	0.00033	rare
Finnish	0.00023	0.00023	rare
European (Non-Finnish)	0.00031	0.00031	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the formation of ganglioside GM3 (alpha-N- acetylneuraminyl-2,3-beta-D-galactosyl-1, 4-beta-D- glucosylceramide). {ECO:0000269|PubMed:16934889}.;
Disease: DISEASE: Salt and pepper developmental regression syndrome (SPDRS) [MIM:609056]: A rare autosomal recessive disorder characterized by infantile onset of severe, recurrent and refractory seizures, failure to thrive, psychomotor delay, developmental stagnation, and cortical blindness. Deafness is observed in some patients. Affected individuals have patches of skin hypo- or hyperpigmentation on the trunk, face, and extremities. {ECO:0000269|PubMed:15502825}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.153

Intolerance Scores

LoFtool: 0.713
RVIS EVS: -0.38
RVIS percentile EVS: 27.69

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.324

Gene Damage Prediction

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