TUSC3

protein-coding

tumor suppressor candidate 3, the group of Oligosaccharyltransferase complex subunits|Solute carrier family 58

Gene summary

This gene encodes a protein that has been associated with several biological functions including cellular magnesium uptake, protein glycosylation and embryonic development. This protein localizes to the endoplasmic reticulum and acts as a component of the oligosaccharyl transferase complex which is responsible for N-linked protein glycosylation. This gene is a candidate tumor suppressor gene. Homozygous mutations in this gene are associated with autosomal recessive nonsyndromic mental retardation-7 and in the proliferation and invasiveness of several cancers including metastatic pancreatic cancer, ovarian cancer and glioblastoma multiform. [provided by RefSeq, Oct 2017]

Previous symbols:

MRT22

MANE transcript

NM_006765.4

Inheritance

ClinVar variants

P:20U:100B:39

Top phenotype

Intellectual developmental disorder, autosomal recessive 7

gnomAD constraint

pLI —, LoF o/e 0.57

Max pathogenic AF

—

Genomic locus

chr8:15,417,215-15,766,649

External References & Databases

Ensembl (ENSG00000104723)

Transcript & Mutation Effects

hg38 • Region Span ~349.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, autosomal recessive 7STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012615

Submitter: PanelApp Australia

autosomal recessive non-syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019502

Submitter: Orphanet

intellectual disabilityDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0001071

Submitter: ClinGen

TUSC3 was first reported in relation to autosomal recessive Intellectual disability in 2008 (Molinari et al. and Garshasbi et al., PMIDs: 18455129, 18452889). At least 9 unique variants (missense, nonsense, large deletions, etc.) have been reported in humans. Of note, large deletions cannot be entered into the Gene Curation Interface at this time but have been observed in probands with Intellectual disability (PMIDs: 28397838, 18452889, 23825019). Case-level evidence supports this gene-disease relationship. In summary, TUSC3 is definitively associated with autosomal recessive Intellectual disability. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

intellectual developmental disorder, autosomal recessive 7DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012615

Submitter: G2P

intellectual developmental disorder, autosomal recessive 7STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012615

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal recessive 7AR

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

Refs: 18452889; 18455129; 21739581

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TUSC3 variants in ClinVar

9 Conditions Cataloged

Intellectual disability, autosomal recessive 7Total: 83

Inborn genetic diseasesTotal: 73

not providedTotal: 42

Congenital disorder of glycosylationTotal: 21

not specifiedTotal: 13

TUSC3-related disorderTotal: 7

Intellectual disabilityTotal: 2

Abnormality of the nervous systemTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006765.4. 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	38 clinvar		42
missense		2 clinvar	84 clinvar	1 clinvar		87
nonsense	3 clinvar	6 clinvar				9
start loss			1 clinvar			1
frameshift	3 clinvar	3 clinvar	1 clinvar			7
splice donor/acceptor (+/-2bp)	1 clinvar	2 clinvar	10 clinvar			13
Total	7	13	100	39	0	159

Highest pathogenic variant AF is 0.00007004442

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 64 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006765.4	RefSeq	NP_006756.2	10	MANE Select
ENST00000503731.6	Ensembl	ENSP00000424544.1	10	MANE Select
NM_001356429.2	RefSeq	NP_001343358.1	10	Standard
NM_001413583.1	RefSeq	NP_001400512.1	10	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)
EMT transition in Colorectal Cancer
Post-translational protein modification
Metabolism of proteins

Biological Process

protein N-linked glycosylation
magnesium ion transport
protein N-linked glycosylation via asparagine
cognition
transmembrane transport

Molecular Function

dolichyl-diphosphooligosaccharide-protein glycotransferase activity
magnesium ion transmembrane transporter activity

Cellular Component

mitochondrion
endoplasmic reticulum membrane
plasma membrane
integral component of plasma membrane
oligosaccharyltransferase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000503731
Coding exons: 10
Length: 349435
Individuals with no LoFs: 125699
Homozygous LoFs: 0
Heterozygous LoFs: 49
Defined: 125748
p: 0.000195

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0491	197	195	1.01	0.0000106	2263
Missense (PolyPhen)		42	58.353	0.71976		657
Synonymous	-3.13	101	68.2	1.48	0.00000350	677
Loss of Function	1.82	12	21.0	0.572	0.00000113	234

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	0.000055	0.000054	rare
Finnish	0.00032	0.00032	rare
European (Non-Finnish)	0.00025	0.00025	rare
South Asian	0.00013	0.00013	rare
Other	0.00069	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Acts as accessory component of the N-oligosaccharyl transferase (OST) complex which catalyzes the transfer of a high mannose oligosaccharide from a lipid-linked oligosaccharide donor to an asparagine residue within an Asn-X-Ser/Thr consensus motif in nascent polypeptide chains. Involved in N-glycosylation of STT3B-dependent substrates. Specifically required for the glycosylation of a subset of acceptor sites that are near cysteine residues; in this function seems to act redundantly with MAGT1. In its oxidized form proposed to form transient mixed disulfides with a glycoprotein substrate to facilitate access of STT3B to the unmodified acceptor site. Has also oxidoreductase-independent functions in the STT3B-containing OST complex possibly involving substrate recognition. {ECO:0000269|PubMed:25135935, ECO:0000305|PubMed:12887896, ECO:0000305|PubMed:24685145}.;

Recessive Scores

pRec: 0.125

Intolerance Scores

LoFtool: 0.635
RVIS EVS: -0.34
RVIS percentile EVS: 30.37

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.536

Gene Damage Prediction

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