rs1050450

chr3-49357401-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000581.4(GPX1):c.599C>T(p.Pro200Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.3 in 1,607,594 control chromosomes in the GnomAD database, including 76,163 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7172 hom., cov: 30)
  • Exomes 𝑓: 0.30 (68991 hom.)
• Consequence: GPX1 NM_000581.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.39

Genes affected

GPX1 (HGNC:4553): (glutathione peroxidase 1) The protein encoded by this gene belongs to the glutathione peroxidase family, members of which catalyze the reduction of organic hydroperoxides and hydrogen peroxide (H2O2) by glutathione, and thereby protect cells against oxidative damage. Other studies indicate that H2O2 is also essential for growth-factor mediated signal transduction, mitochondrial function, and maintenance of thiol redox-balance; therefore, by limiting H2O2 accumulation, glutathione peroxidases are also involved in modulating these processes. Several isozymes of this gene family exist in vertebrates, which vary in cellular location and substrate specificity. This isozyme is the most abundant, is ubiquitously expressed and localized in the cytoplasm, and whose preferred substrate is hydrogen peroxide. It is also a selenoprotein, 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. This gene contains an in-frame GCG trinucleotide repeat in the coding region, and three alleles with 4, 5 or 6 repeats have been found in the human population. The allele with 4 GCG repeats has been significantly associated with breast cancer risk in premenopausal women. Alternatively spliced transcript variants have been found for this gene. Pseudogenes of this locus have been identified on chromosomes X and 21. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.634427E-4).
• BP6: Variant 3-49357401-G-A is Benign according to our data. Variant chr3-49357401-G-A is described in ClinVar as [Benign]. Clinvar id is 16082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-49357401-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.303 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPX1	NM_000581.4	c.599C>T	p.Pro200Leu	missense_variant	2/2	ENST00000419783.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPX1	ENST00000419783.3	c.599C>T	p.Pro200Leu	missense_variant	2/2	1	NM_000581.4	P3

Frequencies

GnomAD3 genomes AF: 0.297 AC: 45043 AN: 151596 Hom.: 7165 Cov.: 30

Gnomad AFR AF: 0.292

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.461

Gnomad EAS AF: 0.0578

Gnomad SAS AF: 0.226

Gnomad FIN AF: 0.472

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.306

Gnomad OTH AF: 0.299

GnomAD3 exomes AF: 0.280 AC: 68269 AN: 244032 Hom.: 11117 AF XY: 0.283 AC XY: 37740 AN XY: 133308

Gnomad AFR exome AF: 0.291

Gnomad AMR exome AF: 0.156

Gnomad ASJ exome AF: 0.455

Gnomad EAS exome AF: 0.0559

Gnomad SAS exome AF: 0.237

Gnomad FIN exome AF: 0.465

Gnomad NFE exome AF: 0.312

Gnomad OTH exome AF: 0.302

GnomAD4 exome AF: 0.300 AC: 436513 AN: 1455880 Hom.: 68991 Cov.: 34 AF XY: 0.299 AC XY: 215897 AN XY: 723240

Gnomad4 AFR exome AF: 0.294

Gnomad4 AMR exome AF: 0.164

Gnomad4 ASJ exome AF: 0.455

Gnomad4 EAS exome AF: 0.0631

Gnomad4 SAS exome AF: 0.243

Gnomad4 FIN exome AF: 0.454

Gnomad4 NFE exome AF: 0.307

Gnomad4 OTH exome AF: 0.304

GnomAD4 genome AF: 0.297 AC: 45072 AN: 151714 Hom.: 7172 Cov.: 30 AF XY: 0.299 AC XY: 22165 AN XY: 74098

Gnomad4 AFR AF: 0.292

Gnomad4 AMR AF: 0.219

Gnomad4 ASJ AF: 0.461

Gnomad4 EAS AF: 0.0581

Gnomad4 SAS AF: 0.226

Gnomad4 FIN AF: 0.472

Gnomad4 NFE AF: 0.306

Gnomad4 OTH AF: 0.297

Alfa AF: 0.322 Hom.: 2756

Bravo AF: 0.277

ESP6500AA AF: 0.273 AC: 983

ESP6500EA AF: 0.294 AC: 2330

ExAC AF: 0.276 AC: 33009

Asia WGS AF: 0.149 AC: 524 AN: 3478

EpiCase AF: 0.317

EpiControl AF: 0.312

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

GLUTATHIONE PEROXIDASE POLYMORPHISM Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Jan 01, 1999

- -

Gluthathione peroxidase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 16, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

This variant is associated with the following publications: (PMID: 27592002, 30256368, 22139612, 21636625, 18563616, 29411539, 11103801, 19826042, 22888637, 20178852, 21165435, 16287877, 20441054, 16956821, 21993316, 19415410, 23073788, 15331559, 16945136, 25047527) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.039	T;.;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.68	T;T;T
MetaRNN	Benign	0.00056	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.34	N;.;.
MutationTaster	Benign	0.079	P;P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.1	N;.;.
REVEL	Benign	0.083
Sift	Benign	0.036	D;.;.
Sift4G	Uncertain	0.060	T;T;.
Polyphen		0.0	B;.;.
Vest4		0.094
MPC		0.79
ClinPred		0.012	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.072

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: rs1050450; hg19: chr3-49394834; COSMIC: COSV69042017; COSMIC: COSV69042017;