MGST3

Chr 1

microsomal glutathione S-transferase 3

Also known as: GST-3, GST-III

NCBI Gene: 4259 ENSG00000143198 UniProt: O14880 OMIM: 604564

The protein catalyzes glutathione conjugation of leukotriene A4 to produce leukotriene C4 and demonstrates glutathione-dependent peroxidase activity toward lipid hydroperoxides, functioning in both cellular detoxification and synthesis of inflammatory mediators. Mutations cause autosomal recessive developmental and epileptic encephalopathy with early infantile onset. The gene shows low constraint to loss-of-function variation.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the MAPEG (Membrane Associated Proteins in Eicosanoid and Glutathione metabolism) protein family. Members of this family are involved in the production of leukotrienes and prostaglandin E, important mediators of inflammation. This gene encodes an enzyme which catalyzes the conjugation of leukotriene A4 and reduced glutathione to produce leukotriene C4. This enzyme also demonstrates glutathione-dependent peroxidase activity towards lipid hydroperoxides.[provided by RefSeq, May 2011]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.25

Clinical Summary— MGST3

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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

21 VUS of 46 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.25LOEUF

pLI 0.000

Z-score 1.00

OE 0.67 (0.38–1.25)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.95Z-score

OE missense 0.72 (0.58–0.88)

64 obs / 89.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.67 (0.38–1.25)

0≤0.351.4

Missense OE?0.72 (0.58–0.88)

0≤0.61.4

Synonymous OE?0.78

0≤1.21.6

LoF obs/exp: 7 / 10.5Missense obs/exp: 64 / 89.3Syn Z: 0.98

This gene — mechanism propensity

0.82top 10%

GOF

0.6640th %ile

LOF

0.2190th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

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

ClinVar Variant Classifications

46 submitted variants in ClinVar

ClinVar

Classification Summary

VUS21

Likely Benign2

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	21	21
Likely Benign	2	2
Benign	0	0
Total	23	23

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

View in ClinVar →

19 pathogenic / likely-pathogenic (of 21) ClinVar copy-number / structural variants overlap MGST3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →