5-151020526-T-C

Variant names:

• chr5-151020526-T-C
• rs8177412
• NM_002084.5:c.-129T>C

Variant summary

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

The NM_002084.5(GPX3):​c.-129T>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 728,610 control chromosomes in the GnomAD database, including 7,191 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 0.15 (1861 hom., cov: 33)
  • Exomes 𝑓: 0.13 (5330 hom.)
• Consequence: GPX3 NM_002084.5 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.152
• Publications: 34 publications found

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

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.2 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002084.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPX3	NM_002084.5	MANE Select	c.-129T>C		upstream_gene	N/A	NP_002075.2
	GPX3	NM_001329790.2		c.-129T>C		upstream_gene	N/A	NP_001316719.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPX3	ENST00000388825.9	TSL:1 MANE Select	c.-129T>C		upstream_gene	N/A	ENSP00000373477.4
	GPX3	ENST00000521650.5	TSL:2	c.-129T>C		upstream_gene	N/A	ENSP00000427873.1
	GPX3	ENST00000517973.1	TSL:3	c.-129T>C		upstream_gene	N/A	ENSP00000429709.1

Frequencies

GnomAD3 genomes AF: 0.151 AC: 23040 AN: 152154 Hom.: 1858 Cov.: 33

Gnomad AFR AF: 0.204

Gnomad AMI AF: 0.248

Gnomad AMR AF: 0.0968

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.172

Gnomad SAS AF: 0.161

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.141

GnomAD4 exome AF: 0.133 AC: 76889 AN: 576338 Hom.: 5330 Cov.: 8 AF XY: 0.135 AC XY: 39814 AN XY: 294246

African (AFR) AF: 0.207 AC: 2773 AN: 13366

American (AMR) AF: 0.0819 AC: 1187 AN: 14486

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 1894 AN: 13906

East Asian (EAS) AF: 0.142 AC: 3942 AN: 27718

South Asian (SAS) AF: 0.168 AC: 7147 AN: 42530

European-Finnish (FIN) AF: 0.115 AC: 3436 AN: 29912

Middle Eastern (MID) AF: 0.192 AC: 420 AN: 2184

European-Non Finnish (NFE) AF: 0.129 AC: 51999 AN: 402380

Other (OTH) AF: 0.137 AC: 4091 AN: 29856

GnomAD4 genome AF: 0.151 AC: 23065 AN: 152272 Hom.: 1861 Cov.: 33 AF XY: 0.149 AC XY: 11068 AN XY: 74474

African (AFR) AF: 0.204 AC: 8478 AN: 41542

American (AMR) AF: 0.0967 AC: 1480 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 432 AN: 3470

East Asian (EAS) AF: 0.172 AC: 893 AN: 5180

South Asian (SAS) AF: 0.161 AC: 779 AN: 4830

European-Finnish (FIN) AF: 0.112 AC: 1187 AN: 10608

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.136 AC: 9234 AN: 68008

Other (OTH) AF: 0.139 AC: 295 AN: 2116

Alfa AF: 0.139 Hom.: 4123

Bravo AF: 0.150

Asia WGS AF: 0.154 AC: 536 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	13
DANN	Benign	0.25
PhyloP100		0.15
PromoterAI		-0.031	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs8177412; hg19: chr5-150400087;