rs3732533

Variant names:

• chr3-126622441-T-C
• rs3732533
• NM_052883.3:c.1367+23A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_052883.3(TXNRD3):​c.1367+23A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0697 in 1,505,454 control chromosomes in the GnomAD database, including 4,247 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.073 (468 hom., cov: 32)
  • Exomes 𝑓: 0.069 (3779 hom.)
• Consequence: TXNRD3 NM_052883.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.923
• Publications: 7 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXNRD3	NM_052883.3	c.1367+23A>G		intron_variant	Intron 11 of 15	ENST00000524230.9	NP_443115.1
TXNRD3	NM_001173513.3	c.1367+23A>G		intron_variant	Intron 11 of 14		NP_001166984.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TXNRD3	ENST00000524230.9	c.1367+23A>G		intron_variant	Intron 11 of 15	1	NM_052883.3	ENSP00000430031.4
TXNRD3	ENST00000523403.3	c.1367+23A>G		intron_variant	Intron 11 of 14	2		ENSP00000429584.3

Frequencies

GnomAD3 genomes AF: 0.0730 AC: 11105 AN: 152128 Hom.: 463 Cov.: 32

Gnomad AFR AF: 0.0602

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0843

Gnomad ASJ AF: 0.0776

Gnomad EAS AF: 0.197

Gnomad SAS AF: 0.0870

Gnomad FIN AF: 0.0843

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0665

Gnomad OTH AF: 0.0722

GnomAD2 exomes AF: 0.0861 AC: 11218 AN: 130328 AF XY: 0.0856

Gnomad AFR exome AF: 0.0583

Gnomad AMR exome AF: 0.0950

Gnomad ASJ exome AF: 0.0734

Gnomad EAS exome AF: 0.203

Gnomad FIN exome AF: 0.0890

Gnomad NFE exome AF: 0.0654

Gnomad OTH exome AF: 0.0761

GnomAD4 exome AF: 0.0694 AC: 93851 AN: 1353208 Hom.: 3779 Cov.: 24 AF XY: 0.0700 AC XY: 46857 AN XY: 669192

African (AFR) AF: 0.0578 AC: 1775 AN: 30710

American (AMR) AF: 0.0956 AC: 3210 AN: 33566

Ashkenazi Jewish (ASJ) AF: 0.0716 AC: 1769 AN: 24706

East Asian (EAS) AF: 0.186 AC: 6602 AN: 35488

South Asian (SAS) AF: 0.0855 AC: 6574 AN: 76928

European-Finnish (FIN) AF: 0.0895 AC: 3023 AN: 33768

Middle Eastern (MID) AF: 0.0613 AC: 344 AN: 5610

European-Non Finnish (NFE) AF: 0.0629 AC: 66395 AN: 1055608

Other (OTH) AF: 0.0732 AC: 4159 AN: 56824

GnomAD4 genome AF: 0.0731 AC: 11126 AN: 152246 Hom.: 468 Cov.: 32 AF XY: 0.0745 AC XY: 5547 AN XY: 74436

African (AFR) AF: 0.0601 AC: 2498 AN: 41548

American (AMR) AF: 0.0850 AC: 1300 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0776 AC: 269 AN: 3468

East Asian (EAS) AF: 0.197 AC: 1019 AN: 5166

South Asian (SAS) AF: 0.0870 AC: 420 AN: 4826

European-Finnish (FIN) AF: 0.0843 AC: 895 AN: 10614

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0665 AC: 4526 AN: 68014

Other (OTH) AF: 0.0743 AC: 157 AN: 2112

Alfa AF: 0.0701 Hom.: 147

Bravo AF: 0.0731

Asia WGS AF: 0.150 AC: 520 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.47
DANN	Benign	0.71
PhyloP100		-0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs3732533; hg19: chr3-126341284; COSMIC: COSV73119809; COSMIC: COSV73119809;