rs8177441

Positions:

• chr5-151026433-G-C

Variant summary

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

The ENST00000388825.9(GPX3):​c.242-467G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.217 in 154,074 control chromosomes in the GnomAD database, including 4,066 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 0.22 (4009 hom., cov: 32)
  • Exomes 𝑓: 0.21 (57 hom.)
• Consequence: GPX3 ENST00000388825.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.964

Genes affected

GPX3 (HGNC:4555): (glutathione peroxidase 3) The protein encoded by this gene belongs to the glutathione peroxidase family, members of which catalyze the reduction of organic hydroperoxides and hydrogen peroxide (H2O2) by glutathione, and thereby protect cells against oxidative damage. Several isozymes of this gene family exist in vertebrates, which vary in cellular location and substrate specificity. This isozyme is secreted, and is abundantly found in plasma. Downregulation of expression of this gene by promoter hypermethylation has been observed in a wide spectrum of human malignancies, including thyroid cancer, hepatocellular carcinoma and chronic myeloid leukemia. This isozyme is also a selenoprotein, containing the rare amino acid selenocysteine (Sec) at its active site. Sec is encoded by the UGA codon, which normally signals translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, designated the Sec insertion sequence (SECIS) element, that is necessary for the recognition of UGA as a Sec codon, rather than as a stop signal. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.559 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPX3	NM_002084.5	c.242-467G>C		intron_variant		ENST00000388825.9	NP_002075.2
GPX3	NM_001329790.2	c.269-467G>C		intron_variant			NP_001316719.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPX3	ENST00000388825.9	c.242-467G>C		intron_variant		1	NM_002084.5	ENSP00000373477	P1

Frequencies

GnomAD3 genomes AF: 0.217 AC: 33008 AN: 151908 Hom.: 4008 Cov.: 32

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.413

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.235

Gnomad EAS AF: 0.576

Gnomad SAS AF: 0.340

Gnomad FIN AF: 0.196

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.191

Gnomad OTH AF: 0.227

GnomAD4 exome AF: 0.209 AC: 428 AN: 2044 Hom.: 57 Cov.: 0 AF XY: 0.206 AC XY: 242 AN XY: 1172

Gnomad4 AFR exome AF: 0.125

Gnomad4 AMR exome AF: 0.238

Gnomad4 ASJ exome AF: 0.257

Gnomad4 EAS exome AF: 0.577

Gnomad4 SAS exome AF: 0.205

Gnomad4 FIN exome AF: 0.150

Gnomad4 NFE exome AF: 0.197

Gnomad4 OTH exome AF: 0.230

GnomAD4 genome AF: 0.217 AC: 33012 AN: 152030 Hom.: 4009 Cov.: 32 AF XY: 0.221 AC XY: 16394 AN XY: 74310

Gnomad4 AFR AF: 0.195

Gnomad4 AMR AF: 0.229

Gnomad4 ASJ AF: 0.235

Gnomad4 EAS AF: 0.576

Gnomad4 SAS AF: 0.339

Gnomad4 FIN AF: 0.196

Gnomad4 NFE AF: 0.191

Gnomad4 OTH AF: 0.224

Alfa AF: 0.207 Hom.: 404

Bravo AF: 0.221

Asia WGS AF: 0.383 AC: 1332 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	8.4
DANN	Benign	0.73

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: rs8177441; hg19: chr5-150405994;