6-28526550-A-G

Variant names:

• chr6-28526550-A-G
• rs445870
• NM_001509.3:c.87+450A>G

Variant summary

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

The NM_001509.3(GPX5):​c.87+450A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 151,894 control chromosomes in the GnomAD database, including 12,425 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 0.39 (12425 hom., cov: 31)
• Consequence: GPX5 NM_001509.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.174
• Publications: 17 publications found

Genes affected

GPX5 (HGNC:4557): (glutathione peroxidase 5) This gene belongs to the glutathione peroxidase family. It is specifically expressed in the epididymis in the mammalian male reproductive tract, and is androgen-regulated. Unlike several other characterized glutathione peroxidases, this enzyme is not a selenoprotein, lacking the selenocysteine residue. Thus, it is selenium-independent, and has been proposed to play a role in protecting the membranes of spermatozoa from the damaging effects of lipid peroxidation and/or preventing premature acrosome reaction. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Oct 2016]

GPX6 (HGNC:4558): (glutathione peroxidase 6) The protein encoded by this gene belongs to the glutathione peroxidase family, members of which catalyze the reduction of hydrogen peroxide, organic hydroperoxides and lipid hydroperoxides, and thereby protect cells against oxidative damage. Several isozymes of this gene family exist in vertebrates, which vary in cellular location and substrate specificity. Expression of this gene has been observed in embryos and olfactory epithelium; however, the exact function of this gene is not known. This isozyme is a selenoprotein in humans, 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. The orthologs of this gene in mouse and rat (and some other species) contain a cysteine (Cys) residue in place of the Sec residue, and their corresponding mRNAs lack SECIS element. [provided by RefSeq, Jul 2017]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.549 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPX5	NM_001509.3	c.87+450A>G		intron_variant	Intron 1 of 4	ENST00000412168.7	NP_001500.1
GPX5	NM_003996.3	c.87+450A>G		intron_variant	Intron 1 of 3		NP_003987.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPX5	ENST00000412168.7	c.87+450A>G		intron_variant	Intron 1 of 4	1	NM_001509.3	ENSP00000392398.2
GPX5	ENST00000469384.1	c.87+450A>G		intron_variant	Intron 1 of 3	1		ENSP00000419935.1
GPX6	ENST00000483058.1	n.306+477T>C		intron_variant	Intron 3 of 4	4

Frequencies

GnomAD3 genomes AF: 0.388 AC: 58905 AN: 151774 Hom.: 12392 Cov.: 31

Gnomad AFR AF: 0.555

Gnomad AMI AF: 0.338

Gnomad AMR AF: 0.364

Gnomad ASJ AF: 0.266

Gnomad EAS AF: 0.516

Gnomad SAS AF: 0.355

Gnomad FIN AF: 0.313

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.304

Gnomad OTH AF: 0.373

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

GnomAD4 genome AF: 0.388 AC: 59003 AN: 151894 Hom.: 12425 Cov.: 31 AF XY: 0.387 AC XY: 28749 AN XY: 74216

African (AFR) AF: 0.555 AC: 22996 AN: 41400

American (AMR) AF: 0.364 AC: 5560 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 921 AN: 3468

East Asian (EAS) AF: 0.515 AC: 2655 AN: 5152

South Asian (SAS) AF: 0.358 AC: 1724 AN: 4816

European-Finnish (FIN) AF: 0.313 AC: 3297 AN: 10538

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.304 AC: 20673 AN: 67950

Other (OTH) AF: 0.370 AC: 779 AN: 2106

Alfa AF: 0.340 Hom.: 20303

Bravo AF: 0.402

Asia WGS AF: 0.400 AC: 1390 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	11
DANN	Benign	0.64
PhyloP100		-0.17
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs445870; hg19: chr6-28494327;