6-28515705-A-C

Position:

• chr6-28515705-A-C

Variant summary

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

The NM_182701.1(GPX6):​c.39T>G​(p.Phe13Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.351 in 1,611,226 control chromosomes in the GnomAD database, including 106,481 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict 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 0.44 (17024 hom., cov: 31)
  • Exomes 𝑓: 0.34 (89457 hom.)
• Consequence: GPX6 NM_182701.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.164

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]

GPX6 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.6888187E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.693 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPX6	NM_182701.1	c.39T>G	p.Phe13Leu	missense_variant	1/5	ENST00000361902.5	NP_874360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPX6	ENST00000361902.5	c.39T>G	p.Phe13Leu	missense_variant	1/5	1	NM_182701.1	ENSP00000354581.1
GPX6	ENST00000474923.1	c.39T>G	p.Phe13Leu	missense_variant	1/4	1		ENSP00000417364.1
GPX6	ENST00000483058.1	n.307-4801T>G		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.442 AC: 67074 AN: 151838 Hom.: 16967 Cov.: 31

Gnomad AFR AF: 0.699

Gnomad AMI AF: 0.340

Gnomad AMR AF: 0.411

Gnomad ASJ AF: 0.311

Gnomad EAS AF: 0.526

Gnomad SAS AF: 0.362

Gnomad FIN AF: 0.315

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.320

Gnomad OTH AF: 0.431

GnomAD3 exomes AF: 0.377 AC: 94022 AN: 249432 Hom.: 19330 AF XY: 0.365 AC XY: 49421 AN XY: 135354

Gnomad AFR exome AF: 0.709

Gnomad AMR exome AF: 0.421

Gnomad ASJ exome AF: 0.336

Gnomad EAS exome AF: 0.541

Gnomad SAS exome AF: 0.360

Gnomad FIN exome AF: 0.318

Gnomad NFE exome AF: 0.313

Gnomad OTH exome AF: 0.343

GnomAD4 exome AF: 0.341 AC: 497596 AN: 1459272 Hom.: 89457 Cov.: 34 AF XY: 0.339 AC XY: 246345 AN XY: 726052

Gnomad4 AFR exome AF: 0.712

Gnomad4 AMR exome AF: 0.422

Gnomad4 ASJ exome AF: 0.331

Gnomad4 EAS exome AF: 0.528

Gnomad4 SAS exome AF: 0.361

Gnomad4 FIN exome AF: 0.318

Gnomad4 NFE exome AF: 0.319

Gnomad4 OTH exome AF: 0.355

GnomAD4 genome AF: 0.442 AC: 67187 AN: 151954 Hom.: 17024 Cov.: 31 AF XY: 0.439 AC XY: 32585 AN XY: 74254

Gnomad4 AFR AF: 0.700

Gnomad4 AMR AF: 0.411

Gnomad4 ASJ AF: 0.311

Gnomad4 EAS AF: 0.526

Gnomad4 SAS AF: 0.365

Gnomad4 FIN AF: 0.315

Gnomad4 NFE AF: 0.320

Gnomad4 OTH AF: 0.427

Alfa AF: 0.346 Hom.: 19094

Bravo AF: 0.465

TwinsUK AF: 0.306 AC: 1135

ALSPAC AF: 0.329 AC: 1267

ESP6500AA AF: 0.668 AC: 2639

ESP6500EA AF: 0.313 AC: 2604

ExAC AF: 0.379 AC: 45837

Asia WGS AF: 0.413 AC: 1436 AN: 3478

EpiCase AF: 0.297

EpiControl AF: 0.308

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.81
DANN	Benign	0.18
DEOGEN2	Benign	0.0063	T;.;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.00021	N
LIST_S2	Benign	0.28	T;T;.
MetaRNN	Benign	0.0000037	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.5	N;.;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.99	N;.;N
REVEL	Benign	0.020
Sift	Benign	1.0	T;.;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.026
MutPred		0.41		Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);
MPC		0.12
ClinPred		0.0026	T
GERP RS		1.5
Varity_R		0.027

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: rs406113; hg19: chr6-28483482; COSMIC: COSV62657397;