chr5-151020661-C-G

Variant names:

• chr5-151020661-C-G
• rs1285059823
• NM_002084.5:c.7C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002084.5(GPX3):​c.7C>G​(p.Arg3Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GPX3 NM_002084.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0660
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14974415).

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.7C>G	p.Arg3Gly	missense	Exon 1 of 5	NP_002075.2
	GPX3	NM_001329790.2		c.7C>G	p.Arg3Gly	missense	Exon 1 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.7C>G	p.Arg3Gly	missense	Exon 1 of 5	ENSP00000373477.4	P22352
	GPX3	ENST00000521650.5	TSL:2	c.7C>G	p.Arg3Gly	missense	Exon 1 of 5	ENSP00000427873.1	E5RG32
	GPX3	ENST00000517973.1	TSL:3	c.7C>G	p.Arg3Gly	missense	Exon 1 of 4	ENSP00000429709.1	A0A182DWH9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456258 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724182

African (AFR) AF: 0.00 AC: 0 AN: 33416

American (AMR) AF: 0.00 AC: 0 AN: 44408

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39590

South Asian (SAS) AF: 0.00 AC: 0 AN: 85684

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5666

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110142

Other (OTH) AF: 0.00 AC: 0 AN: 60160

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.066
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.10
Sift	Benign	0.49	T
Sift4G	Benign	0.13	T
Polyphen		0.0	B
Vest4		0.20
MutPred		0.40		Loss of helix (P = 0.0167)
MVP		0.40
MPC		1.3
ClinPred		0.68	D
GERP RS		-0.45
PromoterAI		0.17	Neutral
Varity_R		0.094
Mutation Taster		=89/11	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

dbSNP: rs1285059823; hg19: chr5-150400222;