12-104315781-C-T

Variant names:

• chr12-104315781-C-T
• rs4964287
• NM_001093771.3:c.615C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001093771.3(TXNRD1):​c.615C>T​(p.Leu205Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.315 in 1,609,308 control chromosomes in the GnomAD database, including 81,370 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. Synonymous variant affecting the same amino acid position (i.e. L205L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.34 (8773 hom., cov: 31)
  • Exomes 𝑓: 0.31 (72597 hom.)
• Consequence: TXNRD1 NM_001093771.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.27
• Publications: 33 publications found

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

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP7: Synonymous conserved (PhyloP=-1.27 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.391 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001093771.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNRD1	NM_001093771.3	MANE Select	c.615C>T	p.Leu205Leu	synonymous	Exon 7 of 17	NP_001087240.1	Q16881-1
	TXNRD1	NM_003330.4		c.321C>T	p.Leu107Leu	synonymous	Exon 5 of 15	NP_003321.3
	TXNRD1	NM_001261445.2		c.315C>T	p.Leu105Leu	synonymous	Exon 5 of 15	NP_001248374.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNRD1	ENST00000525566.6	TSL:1 MANE Select	c.615C>T	p.Leu205Leu	synonymous	Exon 7 of 17	ENSP00000434516.1	Q16881-1
	TXNRD1	ENST00000526691.5	TSL:1	c.321C>T	p.Leu107Leu	synonymous	Exon 5 of 15	ENSP00000435929.1	Q16881-4
	TXNRD1	ENST00000503506.6	TSL:1	c.165C>T	p.Leu55Leu	synonymous	Exon 5 of 15	ENSP00000421934.2	Q16881-5

Frequencies

GnomAD3 genomes AF: 0.335 AC: 50897 AN: 151716 Hom.: 8762 Cov.: 31

Gnomad AFR AF: 0.396

Gnomad AMI AF: 0.319

Gnomad AMR AF: 0.259

Gnomad ASJ AF: 0.326

Gnomad EAS AF: 0.214

Gnomad SAS AF: 0.301

Gnomad FIN AF: 0.423

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.315

Gnomad OTH AF: 0.314

GnomAD2 exomes AF: 0.302 AC: 75120 AN: 248538 AF XY: 0.306

Gnomad AFR exome AF: 0.401

Gnomad AMR exome AF: 0.197

Gnomad ASJ exome AF: 0.299

Gnomad EAS exome AF: 0.213

Gnomad FIN exome AF: 0.410

Gnomad NFE exome AF: 0.315

Gnomad OTH exome AF: 0.305

GnomAD4 exome AF: 0.312 AC: 455326 AN: 1457474 Hom.: 72597 Cov.: 33 AF XY: 0.313 AC XY: 226771 AN XY: 725066

African (AFR) AF: 0.412 AC: 13736 AN: 33350

American (AMR) AF: 0.206 AC: 9160 AN: 44544

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 7982 AN: 25936

East Asian (EAS) AF: 0.239 AC: 9439 AN: 39490

South Asian (SAS) AF: 0.306 AC: 26270 AN: 85984

European-Finnish (FIN) AF: 0.402 AC: 21344 AN: 53120

Middle Eastern (MID) AF: 0.353 AC: 2022 AN: 5736

European-Non Finnish (NFE) AF: 0.313 AC: 346799 AN: 1109236

Other (OTH) AF: 0.309 AC: 18574 AN: 60078

GnomAD4 genome AF: 0.335 AC: 50939 AN: 151834 Hom.: 8773 Cov.: 31 AF XY: 0.338 AC XY: 25109 AN XY: 74196

African (AFR) AF: 0.396 AC: 16388 AN: 41366

American (AMR) AF: 0.258 AC: 3947 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.326 AC: 1129 AN: 3464

East Asian (EAS) AF: 0.214 AC: 1106 AN: 5158

South Asian (SAS) AF: 0.302 AC: 1446 AN: 4796

European-Finnish (FIN) AF: 0.423 AC: 4451 AN: 10518

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.315 AC: 21416 AN: 67950

Other (OTH) AF: 0.312 AC: 657 AN: 2108

Alfa AF: 0.311 Hom.: 15082

Bravo AF: 0.323

Asia WGS AF: 0.260 AC: 907 AN: 3478

EpiCase AF: 0.319

EpiControl AF: 0.320

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.53
DANN	Benign	0.69
PhyloP100		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=97/3	polymorphism (auto)

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: rs4964287; hg19: chr12-104709559; COSMIC: COSV61599371; COSMIC: COSV61599371;