Genetic Variant GPX3:c.*92C>T (chr5-151028222-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002084.5(GPX3):c.*92C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0967 in 1,137,688 control chromosomes in the GnomAD database, including 8,365 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.10 ( 1171 hom., cov: 32)

Exomes 𝑓: 0.096 ( 7194 hom. )

Consequence

GPX3
NM_002084.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.54

Publications

22 publications found

Variant links:

Genes affected

GPX3 (HGNC:4555): (glutathione peroxidase 3) 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. Several isozymes of this gene family exist in vertebrates, which vary in cellular location and substrate specificity. This isozyme is secreted, and is abundantly found in plasma. Downregulation of expression of this gene by promoter hypermethylation has been observed in a wide spectrum of human malignancies, including thyroid cancer, hepatocellular carcinoma and chronic myeloid leukemia. This isozyme 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. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2016]

GPX3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.396 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPX3	NM_002084.5 link	c.*92C>T		3_prime_UTR_variant	Exon 5 of 5	ENST00000388825.9	NP_002075.2
GPX3	NM_001329790.2 link	c.*92C>T		3_prime_UTR_variant	Exon 6 of 6		NP_001316719.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
GPX3	ENST00000388825.9 link	c.*92C>T	3_prime_UTR_variant	Exon 5 of 5	1	NM_002084.5	ENSP00000373477.4
GPX3	ENST00000521632.1 link	c.*58C>T	3_prime_UTR_variant	Exon 3 of 3	5		ENSP00000430743.2
GPX3	ENST00000517973.1 link	c.*316C>T	downstream_gene_variant		3		ENSP00000429709.1
GPX3	ENST00000520059.1 link	c.*314C>T	downstream_gene_variant		3		ENSP00000429314.1

Frequencies

GnomAD3 genomes

AF:

0.102

AC:

15576

AN:

152106

Hom.:

1169

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0845

Gnomad AMI

AF:

0.172

Gnomad AMR

AF:

0.158

Gnomad ASJ

AF:

0.0937

Gnomad EAS

AF:

0.410

Gnomad SAS

AF:

0.201

Gnomad FIN

AF:

0.0819

Gnomad MID

AF:

0.0791

Gnomad NFE

AF:

0.0731

Gnomad OTH

AF:

0.111

GnomAD4 exome

AF:

0.0958

AC:

94394

AN:

985464

Hom.:

7194

Cov.:

AF XY:

0.0986

AC XY:

49156

AN XY:

498640

show subpopulations

African (AFR)

AF:

0.0854

AC:

2037

AN:

23864

American (AMR)

AF:

0.207

AC:

7102

AN:

34280

Ashkenazi Jewish (ASJ)

AF:

0.0858

AC:

1807

AN:

21050

East Asian (EAS)

AF:

0.390

AC:

13243

AN:

33938

South Asian (SAS)

AF:

0.184

AC:

12305

AN:

66940

European-Finnish (FIN)

AF:

0.0906

AC:

4161

AN:

45946

Middle Eastern (MID)

AF:

0.0963

AC:

462

AN:

4796

European-Non Finnish (NFE)

AF:

0.0680

AC:

48281

AN:

710404

Other (OTH)

AF:

0.113

AC:

4996

AN:

44246

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

4413

8826

13239

17652

22065

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1644

3288

4932

6576

8220

<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:

0.102

AC:

15586

AN:

152224

Hom.:

1171

Cov.:

AF XY:

0.108

AC XY:

8023

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.0846

AC:

3514

AN:

41530

American (AMR)

AF:

0.158

AC:

2411

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0937

AC:

325

AN:

3468

East Asian (EAS)

AF:

0.410

AC:

2118

AN:

5162

South Asian (SAS)

AF:

0.201

AC:

968

AN:

4820

European-Finnish (FIN)

AF:

0.0819

AC:

870

AN:

10628

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0731

AC:

4971

AN:

68008

Other (OTH)

AF:

0.110

AC:

232

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

686

1372

2057

2743

3429

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

182

364

546

728

910

<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:

0.0880

Hom.:

3063

Bravo

AF:

0.112

Asia WGS

AF:

0.257

AC:

893

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.35

(source)

DANN

Benign

0.65

PhyloP100

-1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over