rs1044732

Positions:

• chr22-19875619-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006440.5(TXNRD2):​c.*254A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 145,368 control chromosomes in the GnomAD database, including 1,186 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1182 hom., cov: 34)
  • Exomes 𝑓: 0.14 (4 hom.)
• Consequence: TXNRD2 NM_006440.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.30

Genes affected

TXNRD2 (HGNC:18155): (thioredoxin reductase 2) 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 a mitochondrial form important for scavenging reactive oxygen species in mitochondria. 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 encoding different isoforms, including a few localized in the cytosol and some lacking the C-terminal Sec residue, have been found for this gene. [provided by RefSeq, Jun 2017]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 22-19875619-T-C is Benign according to our data. Variant chr22-19875619-T-C is described in ClinVar as [Benign]. Clinvar id is 1261337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.151 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TXNRD2	NM_006440.5	c.*254A>G		3_prime_UTR_variant	18/18	ENST00000400521.7	NP_006431.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TXNRD2	ENST00000400521.7	c.*254A>G		3_prime_UTR_variant	18/18	1	NM_006440.5	ENSP00000383365	P4

Frequencies

GnomAD3 genomes AF: 0.119 AC: 17317 AN: 145112 Hom.: 1177 Cov.: 34

Gnomad AFR AF: 0.0743

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.200

Gnomad EAS AF: 0.0100

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.0922

Gnomad MID AF: 0.159

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.121

GnomAD4 exome AF: 0.138 AC: 22 AN: 160 Hom.: 4 Cov.: 0 AF XY: 0.148 AC XY: 19 AN XY: 128

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.750

Gnomad4 EAS exome AF: 0.00

Gnomad4 NFE exome AF: 0.138

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.119 AC: 17346 AN: 145208 Hom.: 1182 Cov.: 34 AF XY: 0.117 AC XY: 8278 AN XY: 71050

Gnomad4 AFR AF: 0.0747

Gnomad4 AMR AF: 0.108

Gnomad4 ASJ AF: 0.200

Gnomad4 EAS AF: 0.0101

Gnomad4 SAS AF: 0.104

Gnomad4 FIN AF: 0.0922

Gnomad4 NFE AF: 0.154

Gnomad4 OTH AF: 0.122

Alfa AF: 0.147 Hom.: 1730

Bravo AF: 0.110

Asia WGS AF: 0.0670 AC: 232 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	14
DANN	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1044732; hg19: chr22-19863142;