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GeneBe

3-126629435-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_052883.3(TXNRD3):c.1234A>G(p.Lys412Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

TXNRD3
NM_052883.3 missense

Scores

1
3
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.88
Variant links:
Genes affected
TXNRD3 (HGNC:20667): (thioredoxin reductase 3) 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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.40813506).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TXNRD3NM_052883.3 linkuse as main transcriptc.1234A>G p.Lys412Glu missense_variant 10/16 ENST00000524230.9
TXNRD3NM_001173513.3 linkuse as main transcriptc.1234A>G p.Lys412Glu missense_variant 10/15

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TXNRD3ENST00000524230.9 linkuse as main transcriptc.1234A>G p.Lys412Glu missense_variant 10/161 NM_052883.3 P1
TXNRD3ENST00000523403.3 linkuse as main transcriptc.1234A>G p.Lys412Glu missense_variant 10/152

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 08, 2022The c.1234A>G (p.K412E) alteration is located in exon 10 (coding exon 10) of the TXNRD3 gene. This alteration results from a A to G substitution at nucleotide position 1234, causing the lysine (K) at amino acid position 412 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
0.024
T
BayesDel_noAF
Benign
-0.20
Cadd
Uncertain
23
Dann
Uncertain
0.99
Eigen
Benign
-0.084
Eigen_PC
Benign
0.054
FATHMM_MKL
Pathogenic
0.98
D
MetaRNN
Benign
0.41
T;T;T;T
MetaSVM
Benign
-0.84
T
PrimateAI
Uncertain
0.49
T
REVEL
Benign
0.28
Sift4G
Benign
0.31
T;T;.;.
Vest4
0.34
MVP
0.081
ClinPred
0.91
D
GERP RS
4.8
Varity_R
0.44

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-126348278; API