chr6-28531837-T-G

Variant names:

• chr6-28531837-T-G
• NM_001509.3:c.301T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001509.3(GPX5):​c.301T>G​(p.Cys101Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GPX5 NM_001509.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.43
• Publications: 0 publications found

Genes affected

GPX5 (HGNC:4557): (glutathione peroxidase 5) This gene belongs to the glutathione peroxidase family. It is specifically expressed in the epididymis in the mammalian male reproductive tract, and is androgen-regulated. Unlike several other characterized glutathione peroxidases, this enzyme is not a selenoprotein, lacking the selenocysteine residue. Thus, it is selenium-independent, and has been proposed to play a role in protecting the membranes of spermatozoa from the damaging effects of lipid peroxidation and/or preventing premature acrosome reaction. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Oct 2016]

ACMG classification

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, 0.966

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001509.3. 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
	GPX5	NM_001509.3	MANE Select	c.301T>G	p.Cys101Gly	missense	Exon 3 of 5	NP_001500.1	O75715-1
	GPX5	NM_003996.3		c.242-484T>G		intron	N/A	NP_003987.2	O75715-2
	GPX5	NR_144470.2		n.438-484T>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPX5	ENST00000412168.7	TSL:1 MANE Select	c.301T>G	p.Cys101Gly	missense	Exon 3 of 5	ENSP00000392398.2	O75715-1
	GPX5	ENST00000469384.1	TSL:1	c.242-484T>G		intron	N/A	ENSP00000419935.1	O75715-2
	GPX5	ENST00000442674.6	TSL:5	n.676T>G		non_coding_transcript_exon	Exon 4 of 6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.37	T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Benign	0.080	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.51	T
MutationAssessor	Pathogenic	3.9	H
PhyloP100		4.4
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-9.6	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.88		Gain of disorder (P = 0.0103)
MVP		0.63
MPC		0.71
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.98
gMVP		0.79
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: chr6-28499614;