rs58554303

Variant names:

• chr6-28531790-T-C
• rs58554303
• NM_001509.3:c.254T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001509.3(GPX5):​c.254T>C​(p.Leu85Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0217 in 1,610,770 control chromosomes in the GnomAD database, including 461 homozygotes. 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: 𝑓 0.017 (35 hom., cov: 31)
  • Exomes 𝑓: 0.022 (426 hom.)
• Consequence: GPX5 NM_001509.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.51
• Publications: 10 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009439915).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0166 (2531/152248) while in subpopulation NFE AF = 0.0274 (1863/68008). AF 95% confidence interval is 0.0264. There are 35 homozygotes in GnomAd4. There are 1143 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 35 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPX5	NM_001509.3	c.254T>C	p.Leu85Pro	missense_variant	Exon 3 of 5	ENST00000412168.7	NP_001500.1
GPX5	NM_003996.3	c.242-531T>C		intron_variant	Intron 2 of 3		NP_003987.2
GPX5	NR_144470.2	n.438-531T>C		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPX5	ENST00000412168.7	c.254T>C	p.Leu85Pro	missense_variant	Exon 3 of 5	1	NM_001509.3	ENSP00000392398.2
GPX5	ENST00000469384.1	c.242-531T>C		intron_variant	Intron 2 of 3	1		ENSP00000419935.1
GPX5	ENST00000442674.6	n.629T>C		non_coding_transcript_exon_variant	Exon 4 of 6	5
GPX5	ENST00000483784.1	n.433-531T>C		intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes AF: 0.0166 AC: 2531 AN: 152130 Hom.: 35 Cov.: 31

Gnomad AFR AF: 0.00522

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0133

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.00288

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0141

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0274

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.0162 AC: 4034 AN: 249624 AF XY: 0.0159

Gnomad AFR exome AF: 0.00445

Gnomad AMR exome AF: 0.0107

Gnomad ASJ exome AF: 0.0103

Gnomad EAS exome AF: 0.00110

Gnomad FIN exome AF: 0.0141

Gnomad NFE exome AF: 0.0264

Gnomad OTH exome AF: 0.0161

GnomAD4 exome AF: 0.0223 AC: 32502 AN: 1458522 Hom.: 426 Cov.: 30 AF XY: 0.0214 AC XY: 15556 AN XY: 725666

African (AFR) AF: 0.00328 AC: 109 AN: 33246

American (AMR) AF: 0.0112 AC: 494 AN: 44152

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 270 AN: 26072

East Asian (EAS) AF: 0.000681 AC: 27 AN: 39674

South Asian (SAS) AF: 0.00320 AC: 275 AN: 85884

European-Finnish (FIN) AF: 0.0143 AC: 762 AN: 53404

Middle Eastern (MID) AF: 0.00574 AC: 33 AN: 5748

European-Non Finnish (NFE) AF: 0.0266 AC: 29501 AN: 1110082

Other (OTH) AF: 0.0171 AC: 1031 AN: 60260

GnomAD4 genome AF: 0.0166 AC: 2531 AN: 152248 Hom.: 35 Cov.: 31 AF XY: 0.0154 AC XY: 1143 AN XY: 74460

African (AFR) AF: 0.00520 AC: 216 AN: 41536

American (AMR) AF: 0.0133 AC: 203 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 47 AN: 3472

East Asian (EAS) AF: 0.00289 AC: 15 AN: 5188

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4830

European-Finnish (FIN) AF: 0.0141 AC: 149 AN: 10600

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0274 AC: 1863 AN: 68008

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

Alfa AF: 0.0227 Hom.: 109

Bravo AF: 0.0158

TwinsUK AF: 0.0264 AC: 98

ALSPAC AF: 0.0262 AC: 101

ESP6500AA AF: 0.00726 AC: 32

ESP6500EA AF: 0.0217 AC: 187

ExAC AF: 0.0164 AC: 1995

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0234

EpiControl AF: 0.0232

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.89	D
MetaRNN	Benign	0.0094	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Pathogenic	3.9	H
PhyloP100		5.5
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Benign	0.28
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.33
MPC		0.82
ClinPred		0.065	T
GERP RS		2.7
Varity_R		0.98
gMVP		0.93
Mutation Taster		=83/17	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs58554303; hg19: chr6-28499567;