6-28531837-T-G

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 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

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

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPX5	NM_001509.3	c.301T>G	p.Cys101Gly	missense_variant	Exon 3 of 5	ENST00000412168.7	NP_001500.1
GPX5	NM_003996.3	c.242-484T>G		intron_variant	Intron 2 of 3		NP_003987.2
GPX5	NR_144470.2	n.438-484T>G		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPX5	ENST00000412168.7	c.301T>G	p.Cys101Gly	missense_variant	Exon 3 of 5	1	NM_001509.3	ENSP00000392398.2
GPX5	ENST00000469384.1	c.242-484T>G		intron_variant	Intron 2 of 3	1		ENSP00000419935.1
GPX5	ENST00000442674.6	n.676T>G		non_coding_transcript_exon_variant	Exon 4 of 6	5
GPX5	ENST00000483784.1	n.433-484T>G		intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.301T>G (p.C101G) alteration is located in exon 3 (coding exon 3) of the GPX5 gene. This alteration results from a T to G substitution at nucleotide position 301, causing the cysteine (C) at amino acid position 101 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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
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

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-28499614;