12-104286590-T-C

Position:

• chr12-104286590-T-C

Variant summary

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

The NM_001093771.3(TXNRD1):​c.305-2341T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.475 in 359,178 control chromosomes in the GnomAD database, including 36,025 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 0.52 (20271 hom., cov: 29)
  • Exomes 𝑓: 0.45 (15754 hom.)
• Consequence: TXNRD1 NM_001093771.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.03

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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.575 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TXNRD1	NM_001093771.3	c.305-2341T>C		intron_variant		ENST00000525566.6	NP_001087240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TXNRD1	ENST00000525566.6	c.305-2341T>C		intron_variant		1	NM_001093771.3	ENSP00000434516.1
TXNRD1	ENST00000526266.5	c.-209+430T>C		intron_variant		4		ENSP00000431294.1

Frequencies

GnomAD3 genomes AF: 0.516 AC: 77704 AN: 150658 Hom.: 20266 Cov.: 29

Gnomad AFR AF: 0.419

Gnomad AMI AF: 0.616

Gnomad AMR AF: 0.536

Gnomad ASJ AF: 0.562

Gnomad EAS AF: 0.592

Gnomad SAS AF: 0.527

Gnomad FIN AF: 0.418

Gnomad MID AF: 0.585

Gnomad NFE AF: 0.574

Gnomad OTH AF: 0.545

GnomAD4 exome AF: 0.446 AC: 92992 AN: 208408 Hom.: 15754 AF XY: 0.446 AC XY: 43972 AN XY: 98638

Gnomad4 AFR exome AF: 0.317

Gnomad4 AMR exome AF: 0.426

Gnomad4 ASJ exome AF: 0.459

Gnomad4 EAS exome AF: 0.480

Gnomad4 SAS exome AF: 0.404

Gnomad4 FIN exome AF: 0.382

Gnomad4 NFE exome AF: 0.450

Gnomad4 OTH exome AF: 0.436

GnomAD4 genome AF: 0.516 AC: 77730 AN: 150770 Hom.: 20271 Cov.: 29 AF XY: 0.508 AC XY: 37386 AN XY: 73574

Gnomad4 AFR AF: 0.418

Gnomad4 AMR AF: 0.536

Gnomad4 ASJ AF: 0.562

Gnomad4 EAS AF: 0.592

Gnomad4 SAS AF: 0.527

Gnomad4 FIN AF: 0.418

Gnomad4 NFE AF: 0.574

Gnomad4 OTH AF: 0.547

Alfa AF: 0.491 Hom.: 3053

Bravo AF: 0.523

Asia WGS AF: 0.516 AC: 1791 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.5
DANN	Benign	0.48

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: rs4077561; hg19: chr12-104680368; COSMIC: COSV61601966; COSMIC: COSV61601966;