rs58554303

Positions:

• chr6-28531790-T-C

Variant summary

Our verdict is Benign. Variant got -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. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L85V) has been classified as Likely benign.

• 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

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 Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 35 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPX5	NM_001509.3	c.254T>C	p.Leu85Pro	missense_variant	3/5	ENST00000412168.7	NP_001500.1
GPX5	NM_003996.3	c.242-531T>C		intron_variant			NP_003987.2
GPX5	NR_144470.2	n.438-531T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPX5	ENST00000412168.7	c.254T>C	p.Leu85Pro	missense_variant	3/5	1	NM_001509.3	ENSP00000392398	P1
GPX5	ENST00000469384.1	c.242-531T>C		intron_variant		1		ENSP00000419935
GPX5	ENST00000442674.6	n.629T>C		non_coding_transcript_exon_variant	4/6	5
GPX5	ENST00000483784.1	n.433-531T>C		intron_variant, non_coding_transcript_variant		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

GnomAD3 exomes AF: 0.0162 AC: 4034 AN: 249624 Hom.: 38 AF XY: 0.0159 AC XY: 2147 AN XY: 134938

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 SAS exome AF: 0.00271

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

Gnomad4 AFR exome AF: 0.00328

Gnomad4 AMR exome AF: 0.0112

Gnomad4 ASJ exome AF: 0.0104

Gnomad4 EAS exome AF: 0.000681

Gnomad4 SAS exome AF: 0.00320

Gnomad4 FIN exome AF: 0.0143

Gnomad4 NFE exome AF: 0.0266

Gnomad4 OTH exome AF: 0.0171

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

Gnomad4 AFR AF: 0.00520

Gnomad4 AMR AF: 0.0133

Gnomad4 ASJ AF: 0.0135

Gnomad4 EAS AF: 0.00289

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.0141

Gnomad4 NFE AF: 0.0274

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.0231 Hom.: 74

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
MutationTaster	Benign	1.0	D;D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs58554303; hg19: chr6-28499567;