6-28510835-A-G

Position:

• chr6-28510835-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_182701.1(GPX6):​c.157T>C​(p.Tyr53His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00438 in 1,613,210 control chromosomes in the GnomAD database, including 148 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.018 (72 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (76 hom.)
• Consequence: GPX6 NM_182701.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.21

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022250414).
• BP6: Variant 6-28510835-A-G is Benign according to our data. Variant chr6-28510835-A-G is described in ClinVar as [Benign]. Clinvar id is 785161.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0534 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPX6	NM_182701.1	c.157T>C	p.Tyr53His	missense_variant	2/5	ENST00000361902.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPX6	ENST00000361902.5	c.157T>C	p.Tyr53His	missense_variant	2/5	1	NM_182701.1	P1
GPX6	ENST00000474923.1	c.157T>C	p.Tyr53His	missense_variant	2/4	1
GPX6	ENST00000483058.1	n.376T>C		non_coding_transcript_exon_variant	4/5	4

Frequencies

GnomAD3 genomes AF: 0.0179 AC: 2710 AN: 151318 Hom.: 71 Cov.: 33

Gnomad AFR AF: 0.0553

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0168

Gnomad ASJ AF: 0.00866

Gnomad EAS AF: 0.00409

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00127

Gnomad OTH AF: 0.0174

GnomAD3 exomes AF: 0.00605 AC: 1509 AN: 249544 Hom.: 34 AF XY: 0.00496 AC XY: 671 AN XY: 135390

Gnomad AFR exome AF: 0.0531

Gnomad AMR exome AF: 0.00994

Gnomad ASJ exome AF: 0.00913

Gnomad EAS exome AF: 0.00211

Gnomad SAS exome AF: 0.00134

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00125

Gnomad OTH exome AF: 0.00511

GnomAD4 exome AF: 0.00297 AC: 4343 AN: 1461774 Hom.: 76 Cov.: 31 AF XY: 0.00291 AC XY: 2115 AN XY: 727198

Gnomad4 AFR exome AF: 0.0550

Gnomad4 AMR exome AF: 0.0103

Gnomad4 ASJ exome AF: 0.00857

Gnomad4 EAS exome AF: 0.00131

Gnomad4 SAS exome AF: 0.00161

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00102

Gnomad4 OTH exome AF: 0.00709

GnomAD4 genome AF: 0.0179 AC: 2718 AN: 151436 Hom.: 72 Cov.: 33 AF XY: 0.0171 AC XY: 1265 AN XY: 73962

Gnomad4 AFR AF: 0.0553

Gnomad4 AMR AF: 0.0168

Gnomad4 ASJ AF: 0.00866

Gnomad4 EAS AF: 0.00410

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00127

Gnomad4 OTH AF: 0.0172

Alfa AF: 0.00450 Hom.: 20

Bravo AF: 0.0214

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.0474 AC: 189

ESP6500EA AF: 0.00120 AC: 10

ExAC AF: 0.00643 AC: 778

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.00229

EpiControl AF: 0.00267

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 27, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	16
DANN	Benign	0.91
DEOGEN2	Benign	0.0093	T;.;.
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.68	T;T;.
MetaRNN	Benign	0.0022	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.4	M;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.43	N;.;N
REVEL	Benign	0.031
Sift	Benign	0.51	T;.;T
Sift4G	Benign	0.53	T;T;T
Polyphen		0.012	B;.;.
Vest4		0.17
MVP		0.030
MPC		0.14
ClinPred		0.013	T
GERP RS		2.9
Varity_R		0.064

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: rs34825130; hg19: chr6-28478612;