rs4807543

chr19-1106108-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002085.5(GPX4):c.477-134G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0497 in 825,770 control chromosomes in the GnomAD database, including 1,675 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.048 (317 hom., cov: 25)
  • Exomes 𝑓: 0.050 (1358 hom.)
• Consequence: GPX4 NM_002085.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.721

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 19-1106108-G-T is Benign according to our data. Variant chr19-1106108-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 1321762.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.157 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPX4	NM_002085.5	c.477-134G>T		intron_variant		ENST00000354171.13
GPX4	NM_001039847.3	c.477-134G>T		intron_variant
GPX4	NM_001039848.4	c.588-134G>T		intron_variant
GPX4	NM_001367832.1	c.396-134G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPX4	ENST00000354171.13	c.477-134G>T		intron_variant		1	NM_002085.5	P3

Frequencies

GnomAD3 genomes AF: 0.0477 AC: 7063 AN: 148042 Hom.: 318 Cov.: 25

Gnomad AFR AF: 0.0121

Gnomad AMI AF: 0.0385

Gnomad AMR AF: 0.163

Gnomad ASJ AF: 0.0494

Gnomad EAS AF: 0.00160

Gnomad SAS AF: 0.0336

Gnomad FIN AF: 0.0285

Gnomad MID AF: 0.0425

Gnomad NFE AF: 0.0509

Gnomad OTH AF: 0.0586

GnomAD4 exome AF: 0.0501 AC: 33972 AN: 677614 Hom.: 1358 Cov.: 9 AF XY: 0.0493 AC XY: 17251 AN XY: 349686

Gnomad4 AFR exome AF: 0.00968

Gnomad4 AMR exome AF: 0.223

Gnomad4 ASJ exome AF: 0.0522

Gnomad4 EAS exome AF: 0.000968

Gnomad4 SAS exome AF: 0.0407

Gnomad4 FIN exome AF: 0.0327

Gnomad4 NFE exome AF: 0.0494

Gnomad4 OTH exome AF: 0.0495

GnomAD4 genome AF: 0.0476 AC: 7059 AN: 148156 Hom.: 317 Cov.: 25 AF XY: 0.0481 AC XY: 3475 AN XY: 72226

Gnomad4 AFR AF: 0.0121

Gnomad4 AMR AF: 0.162

Gnomad4 ASJ AF: 0.0494

Gnomad4 EAS AF: 0.00161

Gnomad4 SAS AF: 0.0338

Gnomad4 FIN AF: 0.0285

Gnomad4 NFE AF: 0.0509

Gnomad4 OTH AF: 0.0576

Alfa AF: 0.0445 Hom.: 23

Asia WGS AF: 0.0250 AC: 89 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 12, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	0.54
Dann	Benign	0.79
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4807543; hg19: chr19-1106107;