rs777238

Positions:

• chr3-126648797-T-C

Variant summary

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

The NM_052883.3(TXNRD3):​c.244-1501A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.746 in 152,136 control chromosomes in the GnomAD database, including 44,371 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 0.75 (44371 hom., cov: 33)
• Consequence: TXNRD3 NM_052883.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.879

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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.867 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TXNRD3	NM_052883.3	c.244-1501A>G		intron_variant		ENST00000524230.9	NP_443115.1
TXNRD3	NM_001173513.3	c.244-1501A>G		intron_variant			NP_001166984.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TXNRD3	ENST00000524230.9	c.244-1501A>G		intron_variant		1	NM_052883.3	ENSP00000430031.4
TXNRD3	ENST00000523403.3	c.244-1501A>G		intron_variant		2		ENSP00000429584.3

Frequencies

GnomAD3 genomes AF: 0.746 AC: 113429 AN: 152018 Hom.: 44360 Cov.: 33

Gnomad AFR AF: 0.495

Gnomad AMI AF: 0.894

Gnomad AMR AF: 0.834

Gnomad ASJ AF: 0.913

Gnomad EAS AF: 0.673

Gnomad SAS AF: 0.684

Gnomad FIN AF: 0.770

Gnomad MID AF: 0.851

Gnomad NFE AF: 0.873

Gnomad OTH AF: 0.779

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.746 AC: 113487 AN: 152136 Hom.: 44371 Cov.: 33 AF XY: 0.741 AC XY: 55138 AN XY: 74380

Gnomad4 AFR AF: 0.495

Gnomad4 AMR AF: 0.833

Gnomad4 ASJ AF: 0.913

Gnomad4 EAS AF: 0.673

Gnomad4 SAS AF: 0.685

Gnomad4 FIN AF: 0.770

Gnomad4 NFE AF: 0.873

Gnomad4 OTH AF: 0.778

Alfa AF: 0.853 Hom.: 53103

Bravo AF: 0.744

Asia WGS AF: 0.655 AC: 2278 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.5
DANN	Benign	0.69

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: rs777238; hg19: chr3-126367640;