3-49357420-C-T

Position:

chr3-49357420-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000581.4(GPX1):c.580G>A(p.Ala194Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00251 in 1,612,430 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.0096 ( 28 hom., cov: 31)

Exomes 𝑓: 0.0018 ( 32 hom. )

Consequence

GPX1
NM_000581.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.873

Variant links:

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]

GPX1 links:

ENSG00000290318 (HGNC:):

ENSG00000290318 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0057239234).

BP6

Variant 3-49357420-C-T is Benign according to our data. Variant chr3-49357420-C-T is described in ClinVar as [Benign]. Clinvar id is 3055387.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00965 (1468/152186) while in subpopulation AFR AF= 0.032 (1328/41514). AF 95% confidence interval is 0.0306. There are 28 homozygotes in gnomad4. There are 730 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPX1	NM_000581.4 linkuse as main transcript	c.580G>A	p.Ala194Thr	missense_variant	2/2	ENST00000419783.3	NP_000572.2	P07203-1Q7L4Q3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPX1	ENST00000419783.3 linkuse as main transcript	c.580G>A	p.Ala194Thr	missense_variant	2/2	1	NM_000581.4	ENSP00000407375.1		P07203-1
ENSG00000290318	ENST00000704381 linkuse as main transcript	c.*300G>A		3_prime_UTR_variant	6/6			ENSP00000515884.1		A0A994J514

Frequencies

GnomAD3 genomes

AF:

0.00963

AC:

1465

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0320

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00808

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.00814

GnomAD3 exomes

AF:

0.00361

AC:

886

AN:

245164

Hom.:

AF XY:

0.00327

AC XY:

437

AN XY:

133840

show subpopulations

Gnomad AFR exome

AF:

0.0320

Gnomad AMR exome

AF:

0.00241

Gnomad ASJ exome

AF:

0.00392

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00763

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000489

Gnomad OTH exome

AF:

0.00201

GnomAD4 exome

AF:

0.00176

AC:

2574

AN:

1460244

Hom.:

Cov.:

AF XY:

0.00184

AC XY:

1335

AN XY:

726272

show subpopulations

Gnomad4 AFR exome

AF:

0.0328

Gnomad4 AMR exome

AF:

0.00271

Gnomad4 ASJ exome

AF:

0.00394

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00754

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000303

Gnomad4 OTH exome

AF:

0.00355

GnomAD4 genome

AF:

0.00965

AC:

1468

AN:

152186

Hom.:

Cov.:

AF XY:

0.00981

AC XY:

730

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.0320

Gnomad4 AMR

AF:

0.00281

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00788

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.00806

Alfa

AF:

0.00284

Hom.:

Bravo

AF:

0.0105

ESP6500AA

AF:

0.0242

AC:

ESP6500EA

AF:

0.000376

AC:

ExAC

AF:

0.00407

AC:

490

Asia WGS

AF:

0.00722

AC:

AN:

3478

EpiCase

AF:

0.000818

EpiControl

AF:

0.00113

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

GPX1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 25, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.047

T;.;.

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.46

T;T;T

MetaRNN

Benign

0.0057

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.3

L;.;.

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.44

N;.;.

REVEL

Benign

0.036

Sift

Benign

0.58

T;.;.

Sift4G

Benign

0.52

T;T;.

Polyphen

0.0

B;.;.

Vest4

0.12

MVP

0.31

MPC

0.63

ClinPred

0.0023

GERP RS

3.3

Varity_R

0.037

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over