NM_002085.5:c.36G>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_002085.5(GPX4):c.36G>A(p.Pro12Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 1,517,816 control chromosomes in the GnomAD database, including 24,976 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 2418 hom., cov: 34)

Exomes 𝑓: 0.18 ( 22558 hom. )

Consequence

GPX4
NM_002085.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.58

Variant links:

Genes affected

GPX4 (HGNC:4556): (glutathione peroxidase 4) The protein encoded by this gene belongs to the glutathione peroxidase family, members of which catalyze the reduction of hydrogen peroxide, organic hydroperoxides and lipid hydroperoxides, 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 has a high preference for lipid hydroperoxides and protects cells against membrane lipid peroxidation and cell death. It is also required for normal sperm development; thus, it has been identified as a 'moonlighting' protein because of its ability to serve dual functions as a peroxidase, as well as a structural protein in mature spermatozoa. Mutations in this gene are associated with Sedaghatian type of spondylometaphyseal dysplasia (SMDS). 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. Transcript variants resulting from alternative splicing or use of alternate promoters have been described to encode isoforms with different subcellular localization. [provided by RefSeq, Dec 2018]

GPX4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.29).

BP6

Variant 19-1104079-G-A is Benign according to our data. Variant chr19-1104079-G-A is described in ClinVar as [Benign]. Clinvar id is 1258000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.59 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.262 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPX4	NM_002085.5 link	c.36G>A	p.Pro12Pro	synonymous_variant	Exon 1 of 7	ENST00000354171.13	NP_002076.2	P36969-1
GPX4	NM_001039847.3 link	c.36G>A	p.Pro12Pro	synonymous_variant	Exon 1 of 7		NP_001034936.1	P36969
GPX4	NM_001367832.1 link	c.-46G>A		5_prime_UTR_variant	Exon 1 of 7		NP_001354761.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPX4	ENST00000354171.13 link	c.36G>A	p.Pro12Pro	synonymous_variant	Exon 1 of 7	1	NM_002085.5	ENSP00000346103.7		P36969-1

Frequencies

GnomAD3 genomes

AF:

0.155

AC:

23596

AN:

152158

Hom.:

2423

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0353

Gnomad AMI

AF:

0.192

Gnomad AMR

AF:

0.269

Gnomad ASJ

AF:

0.259

Gnomad EAS

AF:

0.130

Gnomad SAS

AF:

0.186

Gnomad FIN

AF:

0.253

Gnomad MID

AF:

0.244

Gnomad NFE

AF:

0.180

Gnomad OTH

AF:

0.170

GnomAD3 exomes

AF:

0.217

AC:

24509

AN:

113144

Hom.:

3035

AF XY:

0.207

AC XY:

13007

AN XY:

62852

show subpopulations

Gnomad AFR exome

AF:

0.0288

Gnomad AMR exome

AF:

0.333

Gnomad ASJ exome

AF:

0.266

Gnomad EAS exome

AF:

0.132

Gnomad SAS exome

AF:

0.189

Gnomad FIN exome

AF:

0.250

Gnomad NFE exome

AF:

0.184

Gnomad OTH exome

AF:

0.187

GnomAD4 exome

AF:

0.176

AC:

240288

AN:

1365540

Hom.:

22558

Cov.:

AF XY:

0.177

AC XY:

119424

AN XY:

673604

show subpopulations

Gnomad4 AFR exome

AF:

0.0295

Gnomad4 AMR exome

AF:

0.319

Gnomad4 ASJ exome

AF:

0.260

Gnomad4 EAS exome

AF:

0.165

Gnomad4 SAS exome

AF:

0.185

Gnomad4 FIN exome

AF:

0.242

Gnomad4 NFE exome

AF:

0.171

Gnomad4 OTH exome

AF:

0.164

GnomAD4 genome

AF:

0.155

AC:

23590

AN:

152276

Hom.:

2418

Cov.:

AF XY:

0.161

AC XY:

11971

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.0353

Gnomad4 AMR

AF:

0.269

Gnomad4 ASJ

AF:

0.259

Gnomad4 EAS

AF:

0.130

Gnomad4 SAS

AF:

0.185

Gnomad4 FIN

AF:

0.253

Gnomad4 NFE

AF:

0.180

Gnomad4 OTH

AF:

0.171

Alfa

AF:

0.175

Hom.:

2275

Bravo

AF:

0.149

Asia WGS

AF:

0.163

AC:

569

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

GPX4-related disorder

Benign:1

Oct 28, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.29

CADD

Benign

4.2

DANN

Benign

0.95

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over