rs4964778

chr12-104292286-C-Gchr12-104292286-C-T

Variant summary

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

The NM_001093771.3(TXNRD1):c.414+3246C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 152,114 control chromosomes in the GnomAD database, including 2,292 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 0.17 (2292 hom., cov: 31)
• Consequence: TXNRD1 NM_001093771.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.540

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 = 0.196 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TXNRD1	NM_001093771.3	c.414+3246C>G		intron_variant		ENST00000525566.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TXNRD1	ENST00000525566.6	c.414+3246C>G		intron_variant		1	NM_001093771.3	P1

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26173 AN: 151996 Hom.: 2291 Cov.: 31

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.265

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.227

Gnomad EAS AF: 0.00366

Gnomad SAS AF: 0.207

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.182

Gnomad OTH AF: 0.180

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

GnomAD4 genome AF: 0.172 AC: 26178 AN: 152114 Hom.: 2292 Cov.: 31 AF XY: 0.172 AC XY: 12800 AN XY: 74378

Gnomad4 AFR AF: 0.180

Gnomad4 AMR AF: 0.127

Gnomad4 ASJ AF: 0.227

Gnomad4 EAS AF: 0.00366

Gnomad4 SAS AF: 0.207

Gnomad4 FIN AF: 0.181

Gnomad4 NFE AF: 0.182

Gnomad4 OTH AF: 0.180

Alfa AF: 0.0796 Hom.: 115

Bravo AF: 0.165

Asia WGS AF: 0.119 AC: 414 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	14
Dann	Benign	0.64

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: rs4964778; hg19: chr12-104686064;