rs773392965

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_002084.5(GPX3):c.127T>G(p.Tyr43Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000162 in 1,608,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

GPX3
NM_002084.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.11

Publications

0 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: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.942

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002084.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPX3	NM_002084.5	MANE Select	c.127T>G	p.Tyr43Asp	missense	Exon 2 of 5	NP_002075.2
	GPX3	NM_001329790.2		c.154T>G	p.Tyr52Asp	missense	Exon 3 of 6	NP_001316719.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GPX3	ENST00000388825.9	TSL:1 MANE Select	c.127T>G	p.Tyr43Asp	missense	Exon 2 of 5	ENSP00000373477.4	P22352
GPX3	ENST00000521632.1	TSL:5	c.34T>G	p.Tyr12Asp	missense	Exon 1 of 3	ENSP00000430743.2	H0YC19
GPX3	ENST00000521650.5	TSL:2	c.154T>G	p.Tyr52Asp	missense	Exon 3 of 5	ENSP00000427873.1	E5RG32

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152054

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000407

AC:

AN:

245510

AF XY:

0.00000750

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000894

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000165

AC:

AN:

1456734

Hom.:

Cov.:

AF XY:

0.0000152

AC XY:

AN XY:

724666

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33240

American (AMR)

AF:

0.00

AC:

AN:

44198

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25944

East Asian (EAS)

AF:

0.00

AC:

AN:

39174

South Asian (SAS)

AF:

0.00

AC:

AN:

85600

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.0000216

AC:

AN:

1109350

Other (OTH)

AF:

0.00

AC:

AN:

60114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000132

AC:

AN:

152054

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74266

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41394

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000827

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Benign

-0.011

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.85

MetaRNN

Pathogenic

0.94

MetaSVM

Benign

-0.72

MutationAssessor

Uncertain

2.9

PhyloP100

7.1

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-5.0

REVEL

Uncertain

0.35

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.021

Polyphen

1.0

Vest4

0.91

MutPred

0.82

Gain of disorder (P = 0.0602)

MVP

0.68

MPC

1.6

ClinPred

0.99

GERP RS

4.6

PromoterAI

0.0088

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.92

Mutation Taster

=68/32

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over