TUSC3

Chr 8

tumor suppressor candidate 3

Also known as: D8S1992, M33, MRT22, MRT7, MagT2, N33, OST3A, SLC58A2

NCBI Gene: 7991 ENSG00000104723 UniProt: Q13454

The TUSC3 protein functions as an accessory component of the N-oligosaccharyl transferase complex in the endoplasmic reticulum, catalyzing N-linked protein glycosylation and facilitating glycosylation of acceptor sites near cysteine residues. Homozygous mutations cause autosomal recessive intellectual developmental disorder, with this gene being extremely intolerant to loss-of-function variants (pLI ~0.000003). The disorder follows an autosomal recessive inheritance pattern.

ResearchSummary from RefSeq, OMIM, UniProt

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]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.93

Clinical Summary— TUSC3

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Gene-Disease Validity (ClinGen)

intellectual disability · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

17 unique Pathogenic / Likely Pathogenic· 128 VUS of 256 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.93LOEUF

pLI 0.000

Z-score 1.82

OE 0.57 (0.36–0.93)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.05Z-score

OE missense 1.01 (0.90–1.14)

197 obs / 195.1 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.57 (0.36–0.93)

0≤0.351.4

Missense OE?1.01 (0.90–1.14)

0≤0.61.4

Synonymous OE?1.48

0≤1.21.6

LoF obs/exp: 12 / 21.0Missense obs/exp: 197 / 195.1Syn Z: -3.13

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveTUSC3-related intellectual developmental disorderLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.75top 25%

GOF

0.6051th %ile

LOF

0.3356th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

256 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7

Likely Pathogenic10

VUS128

Likely Benign58

Benign28

Conflicting6

Pathogenic

Likely Pathogenic

128

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	5	0	2	0	7
Likely Pathogenic	9	1	0	0	10
VUS	2	74	49	3	128
Likely Benign	1	0	24	33	58
Benign	0	0	28	0	28
Conflicting	—				6
Total	17	75	103	36	237

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

32 pathogenic / likely-pathogenic (of 44) ClinVar copy-number / structural variants overlap TUSC3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →