rs6518591

Positions:

• chr22-19936498-A-G

Variant summary

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

The XM_047441689.1(LOC124905081):​c.-363A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 151,980 control chromosomes in the GnomAD database, including 4,478 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 0.23 (4478 hom., cov: 31)
• Consequence: LOC124905081 XM_047441689.1 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.922

Genes affected

LOC124905081 (HGNC:):

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.344 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOC124905081	XM_047441689.1	c.-363A>G		5_prime_UTR_variant	2/2
TXNRD2	NM_006440.5	c.103+5203T>C		intron_variant		ENST00000400521.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TXNRD2	ENST00000400521.7	c.103+5203T>C		intron_variant		1	NM_006440.5	P4
	ENST00000701986.1	n.131+599A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34670 AN: 151862 Hom.: 4471 Cov.: 31

Gnomad AFR AF: 0.348

Gnomad AMI AF: 0.299

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.211

Gnomad EAS AF: 0.0914

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.227

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

GnomAD4 genome AF: 0.228 AC: 34707 AN: 151980 Hom.: 4478 Cov.: 31 AF XY: 0.224 AC XY: 16644 AN XY: 74294

Gnomad4 AFR AF: 0.348

Gnomad4 AMR AF: 0.192

Gnomad4 ASJ AF: 0.211

Gnomad4 EAS AF: 0.0918

Gnomad4 SAS AF: 0.140

Gnomad4 FIN AF: 0.151

Gnomad4 NFE AF: 0.193

Gnomad4 OTH AF: 0.225

Alfa AF: 0.197 Hom.: 6326

Bravo AF: 0.239

Asia WGS AF: 0.110 AC: 386 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.6
DANN	Benign	0.61

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: rs6518591; hg19: chr22-19924021;