rs974334

chr6-28506441-C-Gchr6-28506441-C-T

Variant summary

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

The NM_182701.1(GPX6):c.242-12G>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 1,510,494 control chromosomes in the GnomAD database, including 41,723 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 0.29 (7682 hom., cov: 32)
  • Exomes 𝑓: 0.21 (34041 hom.)
• Consequence: GPX6 NM_182701.1 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001758
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.342

Genes affected

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.494 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPX6	NM_182701.1	c.242-12G>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000361902.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPX6	ENST00000361902.5	c.242-12G>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_182701.1	P1
GPX6	ENST00000474923.1	c.242-12G>C		splice_polypyrimidine_tract_variant, intron_variant		1
GPX6	ENST00000483058.1	n.461-12G>C		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.287 AC: 43582 AN: 151832 Hom.: 7651 Cov.: 32

Gnomad AFR AF: 0.477

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.280

Gnomad ASJ AF: 0.203

Gnomad EAS AF: 0.510

Gnomad SAS AF: 0.345

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.270

GnomAD3 exomes AF: 0.264 AC: 65781 AN: 249536 Hom.: 10451 AF XY: 0.258 AC XY: 34918 AN XY: 135380

Gnomad AFR exome AF: 0.484

Gnomad AMR exome AF: 0.316

Gnomad ASJ exome AF: 0.224

Gnomad EAS exome AF: 0.532

Gnomad SAS exome AF: 0.338

Gnomad FIN exome AF: 0.181

Gnomad NFE exome AF: 0.176

Gnomad OTH exome AF: 0.224

GnomAD4 exome AF: 0.207 AC: 280739 AN: 1358544 Hom.: 34041 Cov.: 22 AF XY: 0.209 AC XY: 142549 AN XY: 681470

Gnomad4 AFR exome AF: 0.491

Gnomad4 AMR exome AF: 0.312

Gnomad4 ASJ exome AF: 0.222

Gnomad4 EAS exome AF: 0.496

Gnomad4 SAS exome AF: 0.340

Gnomad4 FIN exome AF: 0.183

Gnomad4 NFE exome AF: 0.171

Gnomad4 OTH exome AF: 0.226

GnomAD4 genome AF: 0.287 AC: 43664 AN: 151950 Hom.: 7682 Cov.: 32 AF XY: 0.290 AC XY: 21510 AN XY: 74274

Gnomad4 AFR AF: 0.478

Gnomad4 AMR AF: 0.280

Gnomad4 ASJ AF: 0.203

Gnomad4 EAS AF: 0.510

Gnomad4 SAS AF: 0.347

Gnomad4 FIN AF: 0.178

Gnomad4 NFE AF: 0.175

Gnomad4 OTH AF: 0.269

Alfa AF: 0.151 Hom.: 408

Bravo AF: 0.305

Asia WGS AF: 0.379 AC: 1316 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	9.9
Dann	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00018
dbscSNV1_RF	Benign	0.0080
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: rs974334; hg19: chr6-28474218; COSMIC: COSV62657152;