rs777226

Variant names:

• chr3-126631688-C-T
• rs777226
• NM_052883.3:c.971+76G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 10 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=-0.79).
• 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 rank	MANE	Protein	UniProt
TXNRD3	NM_052883.3	c.971+76G>A		intron_variant	Intron 8 of 15	ENST00000524230.9	NP_443115.1
TXNRD3	NM_001173513.3	c.971+76G>A		intron_variant	Intron 8 of 14		NP_001166984.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TXNRD3	ENST00000524230.9	c.971+76G>A		intron_variant	Intron 8 of 15	1	NM_052883.3	ENSP00000430031.4
TXNRD3	ENST00000523403.3	c.971+76G>A		intron_variant	Intron 8 of 14	2		ENSP00000429584.3

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

African (AFR) AF: 0.113 AC: 2037 AN: 18086

American (AMR) AF: 0.324 AC: 9342 AN: 28866

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 3831 AN: 19278

East Asian (EAS) AF: 0.0358 AC: 1148 AN: 32074

South Asian (SAS) AF: 0.160 AC: 9543 AN: 59494

European-Finnish (FIN) AF: 0.162 AC: 5193 AN: 32062

Middle Eastern (MID) AF: 0.199 AC: 844 AN: 4234

European-Non Finnish (NFE) AF: 0.221 AC: 112370 AN: 507322

Other (OTH) AF: 0.202 AC: 7303 AN: 36166

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

African (AFR) AF: 0.115 AC: 4777 AN: 41484

American (AMR) AF: 0.283 AC: 4327 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.213 AC: 739 AN: 3472

East Asian (EAS) AF: 0.0415 AC: 215 AN: 5178

South Asian (SAS) AF: 0.148 AC: 711 AN: 4812

European-Finnish (FIN) AF: 0.148 AC: 1563 AN: 10572

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.224 AC: 15238 AN: 67968

Other (OTH) AF: 0.205 AC: 432 AN: 2110

Alfa AF: 0.209 Hom.: 865

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
PhyloP100		-1.0

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: rs777226; hg19: chr3-126350531;