rs4679274

Positions:

• chr3-126614957-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.1632+398A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.59 in 151,978 control chromosomes in the GnomAD database, including 27,027 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 0.59 (27027 hom., cov: 31)
• Consequence: TXNRD3 NM_052883.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.816

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=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.65 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TXNRD3	NM_052883.3	c.1632+398A>G		intron_variant		ENST00000524230.9	NP_443115.1
TXNRD3	NM_001173513.3	c.1525-3825A>G		intron_variant			NP_001166984.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TXNRD3	ENST00000524230.9	c.1632+398A>G		intron_variant		1	NM_052883.3	ENSP00000430031	P1
TXNRD3	ENST00000523403.3	c.1525-3825A>G		intron_variant		2		ENSP00000429584

Frequencies

GnomAD3 genomes AF: 0.591 AC: 89693 AN: 151860 Hom.: 27028 Cov.: 31

Gnomad AFR AF: 0.470

Gnomad AMI AF: 0.695

Gnomad AMR AF: 0.552

Gnomad ASJ AF: 0.685

Gnomad EAS AF: 0.633

Gnomad SAS AF: 0.555

Gnomad FIN AF: 0.657

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.655

Gnomad OTH AF: 0.594

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

GnomAD4 genome AF: 0.590 AC: 89734 AN: 151978 Hom.: 27027 Cov.: 31 AF XY: 0.591 AC XY: 43902 AN XY: 74256

Gnomad4 AFR AF: 0.470

Gnomad4 AMR AF: 0.551

Gnomad4 ASJ AF: 0.685

Gnomad4 EAS AF: 0.633

Gnomad4 SAS AF: 0.556

Gnomad4 FIN AF: 0.657

Gnomad4 NFE AF: 0.655

Gnomad4 OTH AF: 0.590

Alfa AF: 0.622 Hom.: 9352

Bravo AF: 0.581

Asia WGS AF: 0.562 AC: 1955 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.35
DANN	Benign	0.41

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: rs4679274; hg19: chr3-126333800;