rs4807542

chr19-1104079-G-Achr19-1104079-G-Cchr19-1104079-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002085.5(GPX4):c.36G>A(p.Pro12=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.58

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]

ACMG classification

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/exons	MANE	UniProt
GPX4	NM_002085.5	c.36G>A	p.Pro12=	synonymous_variant	1/7	ENST00000354171.13
GPX4	NM_001039847.3	c.36G>A	p.Pro12=	synonymous_variant	1/7
GPX4	NM_001367832.1	c.-46G>A		5_prime_UTR_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPX4	ENST00000354171.13	c.36G>A	p.Pro12=	synonymous_variant	1/7	1	NM_002085.5	P3

Frequencies

GnomAD3 genomes AF: 0.155 AC: 23596 AN: 152158 Hom.: 2423 Cov.: 34

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

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.: 32 AF XY: 0.177 AC XY: 119424 AN XY: 673604

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.: 34 AF XY: 0.161 AC XY: 11971 AN XY: 74458

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

GPX4-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2019

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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

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

Other links and lift over

dbSNP: rs4807542; hg19: chr19-1104078;