rs777226

Positions:

• chr3-126631688-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_052883.3(TXNRD3):​c.971+76G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 889,664 control chromosomes in the GnomAD database, including 19,646 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 0.19 (2983 hom., cov: 32)
  • Exomes 𝑓: 0.21 (16663 hom.)
• Consequence: TXNRD3 NM_052883.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.03

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.276 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TXNRD3	NM_052883.3	c.971+76G>A		intron_variant		ENST00000524230.9	NP_443115.1
TXNRD3	NM_001173513.3	c.971+76G>A		intron_variant			NP_001166984.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TXNRD3	ENST00000524230.9	c.971+76G>A		intron_variant		1	NM_052883.3	ENSP00000430031	P1
TXNRD3	ENST00000523403.3	c.971+76G>A		intron_variant		2		ENSP00000429584

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28233 AN: 151964 Hom.: 2982 Cov.: 32

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.283

Gnomad ASJ AF: 0.213

Gnomad EAS AF: 0.0414

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.148

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.224

Gnomad OTH AF: 0.202

GnomAD4 exome AF: 0.206 AC: 151611 AN: 737582 Hom.: 16663 AF XY: 0.205 AC XY: 78736 AN XY: 383622

Gnomad4 AFR exome AF: 0.113

Gnomad4 AMR exome AF: 0.324

Gnomad4 ASJ exome AF: 0.199

Gnomad4 EAS exome AF: 0.0358

Gnomad4 SAS exome AF: 0.160

Gnomad4 FIN exome AF: 0.162

Gnomad4 NFE exome AF: 0.221

Gnomad4 OTH exome AF: 0.202

GnomAD4 genome AF: 0.186 AC: 28250 AN: 152082 Hom.: 2983 Cov.: 32 AF XY: 0.181 AC XY: 13480 AN XY: 74352

Gnomad4 AFR AF: 0.115

Gnomad4 AMR AF: 0.283

Gnomad4 ASJ AF: 0.213

Gnomad4 EAS AF: 0.0415

Gnomad4 SAS AF: 0.148

Gnomad4 FIN AF: 0.148

Gnomad4 NFE AF: 0.224

Gnomad4 OTH AF: 0.205

Alfa AF: 0.211 Hom.: 856

Bravo AF: 0.192

Asia WGS AF: 0.114 AC: 396 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.4
DANN	Benign	0.63

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: rs777226; hg19: chr3-126350531;