rs11548

Positions:

• chr5-151028222-C-T

Variant summary

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

The NM_002084.5(GPX3):​c.*92C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0967 in 1,137,688 control chromosomes in the GnomAD database, including 8,365 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 0.10 (1171 hom., cov: 32)
  • Exomes 𝑓: 0.096 (7194 hom.)
• Consequence: GPX3 NM_002084.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.54

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=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.396 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPX3	NM_002084.5	c.*92C>T		3_prime_UTR_variant	5/5	ENST00000388825.9	NP_002075.2
GPX3	NM_001329790.2	c.*92C>T		3_prime_UTR_variant	6/6		NP_001316719.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPX3	ENST00000388825.9	c.*92C>T		3_prime_UTR_variant	5/5	1	NM_002084.5	ENSP00000373477.4
GPX3	ENST00000521632.1	c.*58C>T		3_prime_UTR_variant	3/3	5		ENSP00000430743.2

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15576 AN: 152106 Hom.: 1169 Cov.: 32

Gnomad AFR AF: 0.0845

Gnomad AMI AF: 0.172

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.0937

Gnomad EAS AF: 0.410

Gnomad SAS AF: 0.201

Gnomad FIN AF: 0.0819

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0731

Gnomad OTH AF: 0.111

GnomAD4 exome AF: 0.0958 AC: 94394 AN: 985464 Hom.: 7194 Cov.: 13 AF XY: 0.0986 AC XY: 49156 AN XY: 498640

Gnomad4 AFR exome AF: 0.0854

Gnomad4 AMR exome AF: 0.207

Gnomad4 ASJ exome AF: 0.0858

Gnomad4 EAS exome AF: 0.390

Gnomad4 SAS exome AF: 0.184

Gnomad4 FIN exome AF: 0.0906

Gnomad4 NFE exome AF: 0.0680

Gnomad4 OTH exome AF: 0.113

GnomAD4 genome AF: 0.102 AC: 15586 AN: 152224 Hom.: 1171 Cov.: 32 AF XY: 0.108 AC XY: 8023 AN XY: 74434

Gnomad4 AFR AF: 0.0846

Gnomad4 AMR AF: 0.158

Gnomad4 ASJ AF: 0.0937

Gnomad4 EAS AF: 0.410

Gnomad4 SAS AF: 0.201

Gnomad4 FIN AF: 0.0819

Gnomad4 NFE AF: 0.0731

Gnomad4 OTH AF: 0.110

Alfa AF: 0.0870 Hom.: 1446

Bravo AF: 0.112

Asia WGS AF: 0.257 AC: 893 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.35
DANN	Benign	0.65
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: rs11548; hg19: chr5-150407783; COSMIC: COSV59307025; COSMIC: COSV59307025;