rs3827288

Variant names:

• chr22-19878939-C-T
• rs3827288
• NM_006440.5:c.1276-502G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006440.5(TXNRD2):​c.1276-502G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.173 in 152,230 control chromosomes in the GnomAD database, including 3,018 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 (3018 hom., cov: 33)
• Consequence: TXNRD2 NM_006440.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.218
• Publications: 2 publications found

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]

TXNRD2 Gene-Disease associations (from GenCC):

• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial glucocorticoid deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• glucocorticoid deficiency 5

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.369 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXNRD2	NM_006440.5	c.1276-502G>A		intron_variant	Intron 14 of 17	ENST00000400521.7	NP_006431.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TXNRD2	ENST00000400521.7	c.1276-502G>A		intron_variant	Intron 14 of 17	1	NM_006440.5	ENSP00000383365.1

Frequencies

GnomAD3 genomes AF: 0.173 AC: 26358 AN: 152112 Hom.: 3020 Cov.: 33

Gnomad AFR AF: 0.0402

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.307

Gnomad ASJ AF: 0.195

Gnomad EAS AF: 0.382

Gnomad SAS AF: 0.253

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.194

Gnomad OTH AF: 0.179

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

GnomAD4 genome AF: 0.173 AC: 26350 AN: 152230 Hom.: 3018 Cov.: 33 AF XY: 0.181 AC XY: 13469 AN XY: 74424

African (AFR) AF: 0.0401 AC: 1667 AN: 41558

American (AMR) AF: 0.307 AC: 4687 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 676 AN: 3470

East Asian (EAS) AF: 0.383 AC: 1982 AN: 5176

South Asian (SAS) AF: 0.253 AC: 1223 AN: 4826

European-Finnish (FIN) AF: 0.231 AC: 2445 AN: 10598

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.194 AC: 13203 AN: 67994

Other (OTH) AF: 0.176 AC: 373 AN: 2114

Alfa AF: 0.190 Hom.: 596

Bravo AF: 0.175

Asia WGS AF: 0.283 AC: 982 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	7.0
DANN	Benign	0.83
PhyloP100		-0.22
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs3827288; hg19: chr22-19866462;