Genetic Variant GPX3:c.*249G>C (chr5-151028379-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_002084.5(GPX3):c.*249G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000554 in 360,998 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

GPX3
NM_002084.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.04

Publications

34 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_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPX3	NM_002084.5 link	c.*249G>C		3_prime_UTR_variant	Exon 5 of 5	ENST00000388825.9	NP_002075.2	P22352
GPX3	NM_001329790.2 link	c.*249G>C		3_prime_UTR_variant	Exon 6 of 6		NP_001316719.1	P22352

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
GPX3	ENST00000388825.9 link	c.*249G>C	3_prime_UTR_variant	Exon 5 of 5	1	NM_002084.5	ENSP00000373477.4	P22352
GPX3	ENST00000521632.1 link	c.*215G>C	3_prime_UTR_variant	Exon 3 of 3	5		ENSP00000430743.2	H0YC19
GPX3	ENST00000517973.1 link	c.*473G>C	downstream_gene_variant		3		ENSP00000429709.1	A0A182DWH9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000554

AC:

AN:

360998

Hom.:

Cov.:

AF XY:

0.00000526

AC XY:

AN XY:

190192

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

10660

American (AMR)

AF:

0.00

AC:

AN:

15328

Ashkenazi Jewish (ASJ)

AF:

0.0000894

AC:

AN:

11188

East Asian (EAS)

AF:

0.00

AC:

AN:

23780

South Asian (SAS)

AF:

0.00

AC:

AN:

44136

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21656

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1754

European-Non Finnish (NFE)

AF:

0.00000472

AC:

AN:

211704

Other (OTH)

AF:

0.00

AC:

AN:

20792

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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

Cov.:

Alfa

AF:

0.00

Hom.:

2856

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.030

(source)

DANN

Benign

0.60

PhyloP100

-3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over