19-1104528-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002085.5(GPX4):c.84+401C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00463 in 639,778 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.015 (59 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (20 hom.)
• Consequence: GPX4 NM_002085.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.625

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=-0.79).
• BP6: Variant 19-1104528-C-G is Benign according to our data. Variant chr19-1104528-C-G is described in ClinVar as [Benign]. Clinvar id is 1241253.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.015 (2278/151944) while in subpopulation AFR AF= 0.0509 (2112/41492). AF 95% confidence interval is 0.0491. There are 59 homozygotes in gnomad4. There are 1096 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 58 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPX4	NM_002085.5	c.84+401C>G		intron_variant		ENST00000354171.13
GPX4	NM_001039847.3	c.84+401C>G		intron_variant
GPX4	NM_001367832.1	c.3+401C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPX4	ENST00000354171.13	c.84+401C>G		intron_variant		1	NM_002085.5	P3

Frequencies

GnomAD3 genomes AF: 0.0150 AC: 2271 AN: 151836 Hom.: 58 Cov.: 33

Gnomad AFR AF: 0.0509

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00734

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.000324

Gnomad OTH AF: 0.0139

GnomAD4 exome AF: 0.00140 AC: 681 AN: 487834 Hom.: 20 Cov.: 7 AF XY: 0.00141 AC XY: 325 AN XY: 229964

Gnomad4 AFR exome AF: 0.0531

Gnomad4 AMR exome AF: 0.00396

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000210

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000212

Gnomad4 OTH exome AF: 0.00340

GnomAD4 genome AF: 0.0150 AC: 2278 AN: 151944 Hom.: 59 Cov.: 33 AF XY: 0.0148 AC XY: 1096 AN XY: 74296

Gnomad4 AFR AF: 0.0509

Gnomad4 AMR AF: 0.00733

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000324

Gnomad4 OTH AF: 0.0138

Alfa AF: 0.0105 Hom.: 6

Bravo AF: 0.0174

Asia WGS AF: 0.00680 AC: 23 AN: 3396

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 21, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	5.4
Dann	Benign	0.38

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: rs566928862; hg19: chr19-1104527;