3-126629426-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_052883.3(TXNRD3):c.1243G>A(p.Ala415Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000847 in 1,535,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 9/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000080 ( 0 hom. )
Consequence
TXNRD3
NM_052883.3 missense
NM_052883.3 missense
Scores
2
9
Clinical Significance
Conservation
PhyloP100: 3.91
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 0 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.14976224).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TXNRD3 | NM_052883.3 | c.1243G>A | p.Ala415Thr | missense_variant | 10/16 | ENST00000524230.9 | |
TXNRD3 | NM_001173513.3 | c.1243G>A | p.Ala415Thr | missense_variant | 10/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TXNRD3 | ENST00000524230.9 | c.1243G>A | p.Ala415Thr | missense_variant | 10/16 | 1 | NM_052883.3 | P1 | |
TXNRD3 | ENST00000523403.3 | c.1243G>A | p.Ala415Thr | missense_variant | 10/15 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152166Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000146 AC: 2AN: 136870Hom.: 0 AF XY: 0.0000269 AC XY: 2AN XY: 74418
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GnomAD4 exome AF: 0.00000795 AC: 11AN: 1383272Hom.: 0 Cov.: 30 AF XY: 0.00000733 AC XY: 5AN XY: 682590
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152284Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74468
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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 submitter | clinical testing | Ambry Genetics | Oct 26, 2022 | The c.1243G>A (p.A415T) alteration is located in exon 10 (coding exon 10) of the TXNRD3 gene. This alteration results from a G to A substitution at nucleotide position 1243, causing the alanine (A) at amino acid position 415 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
PrimateAI
Uncertain
T
REVEL
Benign
Sift4G
Benign
T;T;.;.
Vest4
MVP
ClinPred
T
GERP RS
Varity_R
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at