TXNRD3

Chr 3

thioredoxin reductase 3

Also known as: TGR, TR2, TR2IT1, TRXR3, TXNR3, TXNRD3IT1, TXNRD3NB, TXNRD3NT1

NCBI Gene: 114112 ENSG00000197763 UniProt: Q86VQ6 OMIM: 606235

Thioredoxin reductase 3 is a selenocysteine-containing enzyme that catalyzes disulfide bond formation and reduction, functioning in cellular redox homeostasis with highest expression in testis where it promotes sperm maturation. Biallelic mutations cause autosomal recessive spondylometaphyseal dysplasia with cone-rod dystrophy, a skeletal dysplasia syndrome involving growth retardation, spinal abnormalities, and progressive vision loss beginning in childhood. The gene shows tolerance to loss-of-function variants in the general population.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene belongs to the pyridine nucleotide-disulfide oxidoreductase family, and is a member of the thioredoxin (Trx) system. Three thioredoxin reductase (TrxR) isozymes are found in mammals. TrxRs are selenocysteine-containing flavoenzymes, which reduce thioredoxins, as well as other substrates, and play a key role in redox homoeostasis. This gene encodes the third TrxR, which unlike the other two isozymes, contains an additional N-terminal glutaredoxin (Grx) domain, and shows highest expression in testis. The Grx domain allows this isozyme to participate in both Trx and glutathione systems. It functions as a homodimer containing FAD, and selenocysteine (Sec) at the active site. Sec is encoded by UGA codon that normally signals translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, the Sec insertion sequence (SECIS) element, which is necessary for the recognition of UGA as a Sec codon rather than as a stop signal. Alternatively spliced transcript variants have been found for this gene. Experimental evidence suggests the use of a non-AUG (CUG) codon as a translation initiation codon (PMID:20018845). [provided by RefSeq, Aug 2017]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.95

Clinical Summary— TXNRD3

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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

116 VUS of 134 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.95LOEUF

pLI 0.000

Z-score 1.76

OE 0.62 (0.41–0.95)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.60Z-score

OE missense 0.72 (0.64–0.81)

184 obs / 255.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.62 (0.41–0.95)

0≤0.351.4

Missense OE?0.72 (0.64–0.81)

0≤0.61.4

Synonymous OE?0.75

0≤1.21.6

LoF obs/exp: 15 / 24.4Missense obs/exp: 184 / 255.9Syn Z: 1.87

This gene — mechanism propensity

0.76top 25%

GOF

0.77top 25%

LOF

0.2677th %ile

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

GOFprediction above median

DNprediction 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

134 submitted variants in ClinVar

ClinVar

Classification Summary

VUS116

Likely Benign7

Benign1

116

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	96	20	0	116
Likely Benign	6	0	1	7
Benign	0	1	0	1
Total	102	21	1	124

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

View in ClinVar →

12 pathogenic / likely-pathogenic (of 19) ClinVar copy-number / structural variants overlap TXNRD3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →