rs1128446

Positions:

• chr12-104287064-C-G
• chr12-104287064-C-T

Variant summary

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

The ENST00000526691.5(TXNRD1):​c.-273C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 1,415,598 control chromosomes in the GnomAD database, including 37,570 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 0.22 (3725 hom., cov: 33)
  • Exomes 𝑓: 0.23 (33845 hom.)
• Consequence: TXNRD1 ENST00000526691.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.50

Genes affected

TXNRD1 (HGNC:12437): (thioredoxin reductase 1) 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 an ubiquitously expressed, cytosolic form of TrxR, which 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. Alternative splicing, primarily at the 5' end, results in transcript variants encoding same or different isoforms, including a glutaredoxin-containing isoform that is predominantly expressed in testis. [provided by RefSeq, May 2017]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.235 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TXNRD1	NM_001093771.3	c.305-1867C>G		intron_variant		ENST00000525566.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TXNRD1	ENST00000525566.6	c.305-1867C>G		intron_variant		1	NM_001093771.3	P1

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33227 AN: 152044 Hom.: 3721 Cov.: 33

Gnomad AFR AF: 0.234

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.175

Gnomad ASJ AF: 0.275

Gnomad EAS AF: 0.0196

Gnomad SAS AF: 0.246

Gnomad FIN AF: 0.207

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.223

GnomAD4 exome AF: 0.227 AC: 287127 AN: 1263436 Hom.: 33845 Cov.: 33 AF XY: 0.228 AC XY: 139607 AN XY: 612410

Gnomad4 AFR exome AF: 0.243

Gnomad4 AMR exome AF: 0.157

Gnomad4 ASJ exome AF: 0.259

Gnomad4 EAS exome AF: 0.0147

Gnomad4 SAS exome AF: 0.256

Gnomad4 FIN exome AF: 0.191

Gnomad4 NFE exome AF: 0.234

Gnomad4 OTH exome AF: 0.223

GnomAD4 genome AF: 0.219 AC: 33255 AN: 152162 Hom.: 3725 Cov.: 33 AF XY: 0.218 AC XY: 16205 AN XY: 74404

Gnomad4 AFR AF: 0.234

Gnomad4 AMR AF: 0.175

Gnomad4 ASJ AF: 0.275

Gnomad4 EAS AF: 0.0195

Gnomad4 SAS AF: 0.246

Gnomad4 FIN AF: 0.207

Gnomad4 NFE AF: 0.230

Gnomad4 OTH AF: 0.222

Alfa AF: 0.129 Hom.: 234

Bravo AF: 0.213

Asia WGS AF: 0.153 AC: 534 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.7
DANN	Benign	0.58

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: rs1128446; hg19: chr12-104680842;