NM_002084.5:c.538C>T

Variant names:

• chr5-151027987-C-T
• NM_002084.5:c.538C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002084.5(GPX3):​c.538C>T​(p.Arg180Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: GPX3 NM_002084.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.95
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.538C>T	p.Arg180Cys	missense	Exon 5 of 5	NP_002075.2
	GPX3	NM_001329790.2		c.565C>T	p.Arg189Cys	missense	Exon 6 of 6	NP_001316719.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPX3	ENST00000388825.9	TSL:1 MANE Select	c.538C>T	p.Arg180Cys	missense	Exon 5 of 5	ENSP00000373477.4	P22352
	GPX3	ENST00000521632.1	TSL:5	c.345C>T	p.Ser115Ser	synonymous	Exon 3 of 3	ENSP00000430743.2	H0YC19
	GPX3	ENST00000517973.1	TSL:3	c.*81C>T		3_prime_UTR	Exon 4 of 4	ENSP00000429709.1	A0A182DWH9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727248

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000629 AC: 7 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.80	T
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		6.0
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.21
Sift	Benign	0.041	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.96	D
Vest4		0.40
MutPred		0.61		Gain of catalytic residue at W181 (P = 0.0062)
MVP		0.67
MPC		1.4
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.61
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

hg19: chr5-150407548; COSMIC: COSV59303712; COSMIC: COSV59303712;