NM_002085.5:c.477-134G>T

Variant names:

• chr19-1106108-G-T
• rs4807543
• NM_002085.5:c.477-134G>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.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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.721
• Publications: 3 publications found

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]

GPX4 Gene-Disease associations (from GenCC):

• spondylometaphyseal dysplasia, Sedaghatian type

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 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 CliVar as Likely_benign. Clinvar id is 1321762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1106108-G-T is described in CliVar as Likely_benign. Clinvar id is 1321762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1106108-G-T is described in CliVar as Likely_benign. Clinvar id is 1321762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1106108-G-T is described in CliVar as Likely_benign. Clinvar id is 1321762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1106108-G-T is described in CliVar as Likely_benign. Clinvar id is 1321762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1106108-G-T is described in CliVar as Likely_benign. Clinvar id is 1321762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1106108-G-T is described in CliVar as Likely_benign. Clinvar id is 1321762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1106108-G-T is described in CliVar as Likely_benign. Clinvar id is 1321762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1106108-G-T is described in CliVar as Likely_benign. Clinvar id is 1321762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1106108-G-T is described in CliVar as Likely_benign. Clinvar id is 1321762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1106108-G-T is described in CliVar as Likely_benign. Clinvar id is 1321762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1106108-G-T is described in CliVar as Likely_benign. Clinvar id is 1321762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1106108-G-T is described in CliVar as Likely_benign. Clinvar id is 1321762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1106108-G-T is described in CliVar as Likely_benign. Clinvar id is 1321762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1106108-G-T is described in CliVar as Likely_benign. Clinvar id is 1321762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
GPX4	NM_002085.5	c.477-134G>T		intron_variant	Intron 4 of 6	ENST00000354171.13	NP_002076.2
GPX4	NM_001039848.4	c.588-134G>T		intron_variant	Intron 4 of 6		NP_001034937.1
GPX4	NM_001039847.3	c.477-134G>T		intron_variant	Intron 4 of 6		NP_001034936.1
GPX4	NM_001367832.1	c.396-134G>T		intron_variant	Intron 4 of 6		NP_001354761.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPX4	ENST00000354171.13	c.477-134G>T		intron_variant	Intron 4 of 6	1	NM_002085.5	ENSP00000346103.7

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

African (AFR) AF: 0.00968 AC: 167 AN: 17260

American (AMR) AF: 0.223 AC: 4834 AN: 21704

Ashkenazi Jewish (ASJ) AF: 0.0522 AC: 787 AN: 15086

East Asian (EAS) AF: 0.000968 AC: 32 AN: 33056

South Asian (SAS) AF: 0.0407 AC: 2176 AN: 53400

European-Finnish (FIN) AF: 0.0327 AC: 1022 AN: 31254

Middle Eastern (MID) AF: 0.0374 AC: 90 AN: 2406

European-Non Finnish (NFE) AF: 0.0494 AC: 23205 AN: 469916

Other (OTH) AF: 0.0495 AC: 1659 AN: 33532

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

African (AFR) AF: 0.0121 AC: 488 AN: 40330

American (AMR) AF: 0.162 AC: 2388 AN: 14698

Ashkenazi Jewish (ASJ) AF: 0.0494 AC: 169 AN: 3424

East Asian (EAS) AF: 0.00161 AC: 8 AN: 4974

South Asian (SAS) AF: 0.0338 AC: 155 AN: 4582

European-Finnish (FIN) AF: 0.0285 AC: 294 AN: 10318

Middle Eastern (MID) AF: 0.0455 AC: 13 AN: 286

European-Non Finnish (NFE) AF: 0.0509 AC: 3392 AN: 66612

Other (OTH) AF: 0.0576 AC: 118 AN: 2050

Alfa AF: 0.0425 Hom.: 93

Asia WGS AF: 0.0250 AC: 89 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 12, 2021

GeneDx

Significance: Likely 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	-0.80
CADD	Benign	0.54
DANN	Benign	0.79
PhyloP100		-0.72
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4807543; hg19: chr19-1106107;