rs35062161

chr6-28510778-A-T

Variant summary

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

The NM_182701.1(GPX6):c.214T>A(p.Tyr72Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0562 in 1,613,930 control chromosomes in the GnomAD database, including 2,967 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. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.049 (226 hom., cov: 33)
  • Exomes 𝑓: 0.057 (2741 hom.)
• Consequence: GPX6 NM_182701.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.26

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 (MetaRNN=0.004087776).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0614 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPX6	NM_182701.1	c.214T>A	p.Tyr72Asn	missense_variant	2/5	ENST00000361902.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPX6	ENST00000361902.5	c.214T>A	p.Tyr72Asn	missense_variant	2/5	1	NM_182701.1	P1
GPX6	ENST00000474923.1	c.214T>A	p.Tyr72Asn	missense_variant	2/4	1
GPX6	ENST00000483058.1	n.433T>A		non_coding_transcript_exon_variant	4/5	4

Frequencies

GnomAD3 genomes AF: 0.0493 AC: 7495 AN: 152164 Hom.: 226 Cov.: 33

Gnomad AFR AF: 0.0396

Gnomad AMI AF: 0.0877

Gnomad AMR AF: 0.0319

Gnomad ASJ AF: 0.0182

Gnomad EAS AF: 0.00539

Gnomad SAS AF: 0.0143

Gnomad FIN AF: 0.0715

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0629

Gnomad OTH AF: 0.0392

GnomAD3 exomes AF: 0.0447 AC: 11143 AN: 249386 Hom.: 375 AF XY: 0.0439 AC XY: 5942 AN XY: 135292

Gnomad AFR exome AF: 0.0376

Gnomad AMR exome AF: 0.0235

Gnomad ASJ exome AF: 0.0194

Gnomad EAS exome AF: 0.00517

Gnomad SAS exome AF: 0.0107

Gnomad FIN exome AF: 0.0761

Gnomad NFE exome AF: 0.0640

Gnomad OTH exome AF: 0.0421

GnomAD4 exome AF: 0.0570 AC: 83286 AN: 1461648 Hom.: 2741 Cov.: 31 AF XY: 0.0554 AC XY: 40295 AN XY: 727136

Gnomad4 AFR exome AF: 0.0375

Gnomad4 AMR exome AF: 0.0251

Gnomad4 ASJ exome AF: 0.0203

Gnomad4 EAS exome AF: 0.00264

Gnomad4 SAS exome AF: 0.0104

Gnomad4 FIN exome AF: 0.0740

Gnomad4 NFE exome AF: 0.0652

Gnomad4 OTH exome AF: 0.0470

GnomAD4 genome AF: 0.0492 AC: 7493 AN: 152282 Hom.: 226 Cov.: 33 AF XY: 0.0483 AC XY: 3597 AN XY: 74466

Gnomad4 AFR AF: 0.0395

Gnomad4 AMR AF: 0.0319

Gnomad4 ASJ AF: 0.0182

Gnomad4 EAS AF: 0.00541

Gnomad4 SAS AF: 0.0141

Gnomad4 FIN AF: 0.0715

Gnomad4 NFE AF: 0.0629

Gnomad4 OTH AF: 0.0388

Alfa AF: 0.0545 Hom.: 185

Bravo AF: 0.0472

TwinsUK AF: 0.0636 AC: 236

ALSPAC AF: 0.0656 AC: 253

ESP6500AA AF: 0.0397 AC: 160

ESP6500EA AF: 0.0620 AC: 517

ExAC AF: 0.0458 AC: 5539

Asia WGS AF: 0.0130 AC: 44 AN: 3478

EpiCase AF: 0.0519

EpiControl AF: 0.0576

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.58
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Benign	0.0096	T;.;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;T;.
MetaRNN	Benign	0.0033	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.2	L;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-4.7	D;.;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0010	D;.;T
Sift4G	Uncertain	0.031	D;D;T
Polyphen		0.99	D;.;.
Vest4		0.46
MPC		0.65
ClinPred		0.070	T
GERP RS		4.1
Varity_R		0.51

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: rs35062161; hg19: chr6-28478555; COSMIC: COSV62659308;