rs3805435

Positions:

• chr5-151021735-T-C

Variant summary

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

The NM_002084.5(GPX3):​c.87+994T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0907 in 152,858 control chromosomes in the GnomAD database, including 1,148 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 0.091 (1141 hom., cov: 32)
  • Exomes 𝑓: 0.096 (7 hom.)
• Consequence: GPX3 NM_002084.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.46

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=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPX3	NM_002084.5	c.87+994T>C		intron_variant		ENST00000388825.9	NP_002075.2
GPX3	NM_001329790.2	c.114+881T>C		intron_variant			NP_001316719.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPX3	ENST00000388825.9	c.87+994T>C		intron_variant		1	NM_002084.5	ENSP00000373477	P1

Frequencies

GnomAD3 genomes AF: 0.0908 AC: 13793 AN: 151956 Hom.: 1142 Cov.: 32

Gnomad AFR AF: 0.0191

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.167

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.417

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.0821

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0839

Gnomad OTH AF: 0.0999

GnomAD4 exome AF: 0.0957 AC: 75 AN: 784 Hom.: 7 Cov.: 0 AF XY: 0.0950 AC XY: 38 AN XY: 400

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.182

Gnomad4 ASJ exome AF: 0.143

Gnomad4 EAS exome AF: 0.293

Gnomad4 FIN exome AF: 0.0400

Gnomad4 NFE exome AF: 0.0680

Gnomad4 OTH exome AF: 0.146

GnomAD4 genome AF: 0.0907 AC: 13788 AN: 152074 Hom.: 1141 Cov.: 32 AF XY: 0.0958 AC XY: 7120 AN XY: 74342

Gnomad4 AFR AF: 0.0191

Gnomad4 AMR AF: 0.167

Gnomad4 ASJ AF: 0.107

Gnomad4 EAS AF: 0.417

Gnomad4 SAS AF: 0.199

Gnomad4 FIN AF: 0.0821

Gnomad4 NFE AF: 0.0839

Gnomad4 OTH AF: 0.0989

Alfa AF: 0.0895 Hom.: 650

Bravo AF: 0.0978

Asia WGS AF: 0.260 AC: 903 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.84
DANN	Benign	0.85

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: rs3805435; hg19: chr5-150401296;