dbSNP rs6446261: GPX1:p.Ala194Thr (chr3-49357420-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

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

Publications

14 publications found

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 was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 28 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000581.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GPX1	NM_000581.4	MANE Select	c.580G>A	p.Ala194Thr	missense	Exon 2 of 2	NP_000572.2
GPX1	NM_001329455.2		c.442G>A	p.Ala148Thr	missense	Exon 2 of 2	NP_001316384.1	A0A2R8Y6B6
GPX1	NM_001329503.2		c.*86G>A		3_prime_UTR	Exon 2 of 2	NP_001316432.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GPX1	ENST00000419783.3	TSL:1 MANE Select	c.580G>A	p.Ala194Thr	missense	Exon 2 of 2	ENSP00000407375.1	P07203-1
ENSG00000290318	ENST00000704381.1		c.*300G>A		3_prime_UTR	Exon 6 of 6	ENSP00000515884.1	A0A994J514
GPX1	ENST00000703795.1		c.577G>A	p.Ala193Thr	missense	Exon 2 of 2	ENSP00000515480.1	A0A994J430

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

GnomAD2 exomes

AF:

0.00361

AC:

886

AN:

245164

AF XY:

0.00327

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 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

African (AFR)

AF:

0.0328

AC:

1096

AN:

33464

American (AMR)

AF:

0.00271

AC:

121

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00394

AC:

103

AN:

26124

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39678

South Asian (SAS)

AF:

0.00754

AC:

650

AN:

86232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52908

Middle Eastern (MID)

AF:

0.00901

AC:

AN:

5662

European-Non Finnish (NFE)

AF:

0.000303

AC:

337

AN:

1111140

Other (OTH)

AF:

0.00355

AC:

214

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

145

289

434

578

723

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00965

AC:

1468

AN:

152186

Hom.:

Cov.:

AF XY:

0.00981

AC XY:

730

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.0320

AC:

1328

AN:

41514

American (AMR)

AF:

0.00281

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00788

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000397

AC:

AN:

68016

Other (OTH)

AF:

0.00806

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

123

185

246

308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00440

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

ClinVar submissions

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

GPX1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.047

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.46

MetaRNN

Benign

0.0057

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.3

PhyloP100

0.87

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.44

REVEL

Benign

0.036

Sift

Benign

0.58

Sift4G

Benign

0.52

Polyphen

0.0

Vest4

0.12

MVP

0.31

MPC

0.63

ClinPred

0.0023

GERP RS

3.3

Varity_R

0.037

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over