3-126611067-A-G

Variant names:

• chr3-126611067-A-G
• rs777241
• NM_052883.3:c.1698T>C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_052883.3(TXNRD3):​c.1698T>C​(p.Tyr566Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.95 in 1,521,238 control chromosomes in the GnomAD database, including 687,902 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 0.94 (67882 hom., cov: 33)
  • Exomes 𝑓: 0.95 (620020 hom.)
• Consequence: TXNRD3 NM_052883.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.25

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

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP7: Synonymous conserved (PhyloP=-1.25 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.957 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXNRD3	NM_052883.3	c.1698T>C	p.Tyr566Tyr	synonymous_variant	Exon 14 of 16	ENST00000524230.9	NP_443115.1
TXNRD3	NM_001173513.3	c.1590T>C	p.Tyr530Tyr	synonymous_variant	Exon 13 of 15		NP_001166984.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TXNRD3	ENST00000524230.9	c.1698T>C	p.Tyr566Tyr	synonymous_variant	Exon 14 of 16	1	NM_052883.3	ENSP00000430031.4
TXNRD3	ENST00000523403.3	c.1590T>C	p.Tyr530Tyr	synonymous_variant	Exon 13 of 15	2		ENSP00000429584.3

Frequencies

GnomAD3 genomes AF: 0.943 AC: 143577 AN: 152208 Hom.: 67817 Cov.: 33

Gnomad AFR AF: 0.932

Gnomad AMI AF: 0.920

Gnomad AMR AF: 0.969

Gnomad ASJ AF: 0.994

Gnomad EAS AF: 0.874

Gnomad SAS AF: 0.793

Gnomad FIN AF: 0.907

Gnomad MID AF: 0.978

Gnomad NFE AF: 0.964

Gnomad OTH AF: 0.939

GnomAD3 exomes AF: 0.931 AC: 122331 AN: 131394 Hom.: 57243 AF XY: 0.923 AC XY: 66106 AN XY: 71602

Gnomad AFR exome AF: 0.931

Gnomad AMR exome AF: 0.979

Gnomad ASJ exome AF: 0.994

Gnomad EAS exome AF: 0.872

Gnomad SAS exome AF: 0.810

Gnomad FIN exome AF: 0.908

Gnomad NFE exome AF: 0.962

Gnomad OTH exome AF: 0.952

GnomAD4 exome AF: 0.951 AC: 1301519 AN: 1368912 Hom.: 620020 Cov.: 32 AF XY: 0.947 AC XY: 639488 AN XY: 675394

Gnomad4 AFR exome AF: 0.932

Gnomad4 AMR exome AF: 0.978

Gnomad4 ASJ exome AF: 0.993

Gnomad4 EAS exome AF: 0.896

Gnomad4 SAS exome AF: 0.806

Gnomad4 FIN exome AF: 0.913

Gnomad4 NFE exome AF: 0.963

Gnomad4 OTH exome AF: 0.944

GnomAD4 genome AF: 0.943 AC: 143701 AN: 152326 Hom.: 67882 Cov.: 33 AF XY: 0.939 AC XY: 69905 AN XY: 74480

Gnomad4 AFR AF: 0.932

Gnomad4 AMR AF: 0.969

Gnomad4 ASJ AF: 0.994

Gnomad4 EAS AF: 0.874

Gnomad4 SAS AF: 0.794

Gnomad4 FIN AF: 0.907

Gnomad4 NFE AF: 0.964

Gnomad4 OTH AF: 0.940

Alfa AF: 0.964 Hom.: 70974

Bravo AF: 0.952

Asia WGS AF: 0.848 AC: 2950 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.061
DANN	Benign	0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs777241; hg19: chr3-126329910;