ENST00000588919.5:c.*270T>G

Variant names:

• chr19-1107036-T-G
• rs2074451
• ENST00000588919.5:c.*270T>G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000588919.5(GPX4):​c.*270T>G variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.598 in 152,182 control chromosomes in the GnomAD database, including 27,723 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 0.60 (27723 hom., cov: 35)
• Consequence: GPX4 ENST00000588919.5 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.24

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.711 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPX4	ENST00000588919.5	c.*270T>G		downstream_gene_variant		2		ENSP00000464989.3
GPX4	ENST00000592940.2	n.*245T>G		downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.598 AC: 90912 AN: 152064 Hom.: 27682 Cov.: 35

Gnomad AFR AF: 0.718

Gnomad AMI AF: 0.774

Gnomad AMR AF: 0.626

Gnomad ASJ AF: 0.508

Gnomad EAS AF: 0.549

Gnomad SAS AF: 0.555

Gnomad FIN AF: 0.625

Gnomad MID AF: 0.544

Gnomad NFE AF: 0.524

Gnomad OTH AF: 0.577

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.598 AC: 91013 AN: 152182 Hom.: 27723 Cov.: 35 AF XY: 0.603 AC XY: 44854 AN XY: 74390

Gnomad4 AFR AF: 0.718

Gnomad4 AMR AF: 0.626

Gnomad4 ASJ AF: 0.508

Gnomad4 EAS AF: 0.549

Gnomad4 SAS AF: 0.554

Gnomad4 FIN AF: 0.625

Gnomad4 NFE AF: 0.524

Gnomad4 OTH AF: 0.581

Alfa AF: 0.530 Hom.: 27196

Bravo AF: 0.602

Asia WGS AF: 0.599 AC: 2082 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.45
DANN	Benign	0.77

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2074451; hg19: chr19-1107035;