chr19-1104564-G-T

Variant names:

• chr19-1104564-G-T
• rs57563163
• NM_002085.5:c.84+437G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002085.5(GPX4):​c.84+437G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 918,534 control chromosomes in the GnomAD database, including 751 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (529 hom., cov: 33)
  • Exomes 𝑓: 0.0037 (222 hom.)
• Consequence: GPX4 NM_002085.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.96

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 19-1104564-G-T is Benign according to our data. Variant chr19-1104564-G-T is described in ClinVar as [Benign]. Clinvar id is 1231737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPX4	NM_002085.5	c.84+437G>T		intron_variant	Intron 1 of 6	ENST00000354171.13	NP_002076.2
GPX4	NM_001039847.3	c.84+437G>T		intron_variant	Intron 1 of 6		NP_001034936.1
GPX4	NM_001367832.1	c.3+437G>T		intron_variant	Intron 1 of 6		NP_001354761.1
GPX4	NM_001039848.4	c.-171G>T		upstream_gene_variant			NP_001034937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPX4	ENST00000354171.13	c.84+437G>T		intron_variant	Intron 1 of 6	1	NM_002085.5	ENSP00000346103.7

Frequencies

GnomAD3 genomes AF: 0.0469 AC: 7121 AN: 151760 Hom.: 530 Cov.: 33

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0168

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000589

Gnomad OTH AF: 0.0254

GnomAD4 exome AF: 0.00373 AC: 2857 AN: 766666 Hom.: 222 Cov.: 11 AF XY: 0.00344 AC XY: 1224 AN XY: 355992

Gnomad4 AFR exome AF: 0.170 AC: 2507 AN: 14712

Gnomad4 AMR exome AF: 0.00795 AC: 9 AN: 1132

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 5116

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 3836

Gnomad4 SAS exome AF: 0.000199 AC: 3 AN: 15098

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 670

Gnomad4 NFE exome AF: 0.000186 AC: 130 AN: 699120

Gnomad4 Remaining exome AF: 0.00787 AC: 200 AN: 25412

GnomAD4 genome AF: 0.0470 AC: 7136 AN: 151868 Hom.: 529 Cov.: 33 AF XY: 0.0454 AC XY: 3372 AN XY: 74250

Gnomad4 AFR AF: 0.163 AC: 0.163265 AN: 0.163265

Gnomad4 AMR AF: 0.0167 AC: 0.0166929 AN: 0.0166929

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000622 AC: 0.000622148 AN: 0.000622148

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000589 AC: 0.000589258 AN: 0.000589258

Gnomad4 OTH AF: 0.0256 AC: 0.025641 AN: 0.025641

Alfa AF: 0.000600 Hom.: 1

Bravo AF: 0.0534

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.2
DANN	Benign	0.66
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		3.5
Mutation Taster		=100/0	polymorphism (auto)

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: rs57563163; hg19: chr19-1104563;