19-1104439-G-C

Position:

• chr19-1104439-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002085.5(GPX4):​c.84+312G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0566 in 377,856 control chromosomes in the GnomAD database, including 1,255 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.052 (413 hom., cov: 33)
  • Exomes 𝑓: 0.060 (842 hom.)
• Consequence: GPX4 NM_002085.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.00100

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-1104439-G-C is Benign according to our data. Variant chr19-1104439-G-C is described in ClinVar as [Benign]. Clinvar id is 1174251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.238 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPX4	NM_002085.5	c.84+312G>C		intron_variant		ENST00000354171.13	NP_002076.2
GPX4	NM_001039847.3	c.84+312G>C		intron_variant			NP_001034936.1
GPX4	NM_001367832.1	c.3+312G>C		intron_variant			NP_001354761.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPX4	ENST00000354171.13	c.84+312G>C		intron_variant		1	NM_002085.5	ENSP00000346103	P3

Frequencies

GnomAD3 genomes AF: 0.0515 AC: 7830 AN: 151992 Hom.: 412 Cov.: 33

Gnomad AFR AF: 0.0115

Gnomad AMI AF: 0.0419

Gnomad AMR AF: 0.0424

Gnomad ASJ AF: 0.0444

Gnomad EAS AF: 0.249

Gnomad SAS AF: 0.163

Gnomad FIN AF: 0.0513

Gnomad MID AF: 0.0573

Gnomad NFE AF: 0.0553

Gnomad OTH AF: 0.0602

GnomAD4 exome AF: 0.0601 AC: 13558 AN: 225756 Hom.: 842 Cov.: 5 AF XY: 0.0601 AC XY: 6781 AN XY: 112918

Gnomad4 AFR exome AF: 0.0101

Gnomad4 AMR exome AF: 0.0251

Gnomad4 ASJ exome AF: 0.0403

Gnomad4 EAS exome AF: 0.232

Gnomad4 SAS exome AF: 0.121

Gnomad4 FIN exome AF: 0.0372

Gnomad4 NFE exome AF: 0.0486

Gnomad4 OTH exome AF: 0.0540

GnomAD4 genome AF: 0.0515 AC: 7836 AN: 152100 Hom.: 413 Cov.: 33 AF XY: 0.0555 AC XY: 4128 AN XY: 74362

Gnomad4 AFR AF: 0.0115

Gnomad4 AMR AF: 0.0424

Gnomad4 ASJ AF: 0.0444

Gnomad4 EAS AF: 0.250

Gnomad4 SAS AF: 0.163

Gnomad4 FIN AF: 0.0513

Gnomad4 NFE AF: 0.0553

Gnomad4 OTH AF: 0.0629

Alfa AF: 0.0519 Hom.: 30

Bravo AF: 0.0458

Asia WGS AF: 0.182 AC: 624 AN: 3436

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	-0.81
CADD	Benign	5.6
DANN	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.5

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: rs2074450; hg19: chr19-1104438;