rs2075710

Variant names:

• chr19-1106846-C-T
• rs2075710
• NM_002085.5:c.*274C>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.*274C>T variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 543,604 control chromosomes in the GnomAD database, including 23,574 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9983 hom., cov: 34)
  • Exomes 𝑓: 0.25 (13591 hom.)
• Consequence: GPX4 NM_002085.5 downstream_gene
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.348
• Publications: 15 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=-0.89).
• BP6: Variant 19-1106846-C-T is Benign according to our data. Variant chr19-1106846-C-T is described in ClinVar as Benign. ClinVar VariationId is 1261068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.537 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPX4	NM_002085.5	c.*274C>T		downstream_gene_variant		ENST00000354171.13	NP_002076.2
GPX4	NM_001039848.4	c.*274C>T		downstream_gene_variant			NP_001034937.1
GPX4	NM_001039847.3	c.*206C>T		downstream_gene_variant			NP_001034936.1
GPX4	NM_001367832.1	c.*274C>T		downstream_gene_variant			NP_001354761.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPX4	ENST00000354171.13	c.*274C>T		downstream_gene_variant		1	NM_002085.5	ENSP00000346103.7

Frequencies

GnomAD3 genomes AF: 0.336 AC: 51071 AN: 151972 Hom.: 9970 Cov.: 34

Gnomad AFR AF: 0.543

Gnomad AMI AF: 0.289

Gnomad AMR AF: 0.361

Gnomad ASJ AF: 0.288

Gnomad EAS AF: 0.129

Gnomad SAS AF: 0.221

Gnomad FIN AF: 0.280

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.241

Gnomad OTH AF: 0.313

GnomAD4 exome AF: 0.255 AC: 99830 AN: 391514 Hom.: 13591 AF XY: 0.253 AC XY: 51555 AN XY: 203826

African (AFR) AF: 0.534 AC: 5749 AN: 10764

American (AMR) AF: 0.375 AC: 4905 AN: 13064

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 3710 AN: 12612

East Asian (EAS) AF: 0.172 AC: 4730 AN: 27484

South Asian (SAS) AF: 0.234 AC: 7630 AN: 32656

European-Finnish (FIN) AF: 0.262 AC: 7354 AN: 28108

Middle Eastern (MID) AF: 0.243 AC: 438 AN: 1802

European-Non Finnish (NFE) AF: 0.245 AC: 59261 AN: 241646

Other (OTH) AF: 0.259 AC: 6053 AN: 23378

GnomAD4 genome AF: 0.336 AC: 51124 AN: 152090 Hom.: 9983 Cov.: 34 AF XY: 0.335 AC XY: 24936 AN XY: 74340

African (AFR) AF: 0.543 AC: 22544 AN: 41492

American (AMR) AF: 0.360 AC: 5509 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 999 AN: 3468

East Asian (EAS) AF: 0.128 AC: 664 AN: 5170

South Asian (SAS) AF: 0.221 AC: 1064 AN: 4822

European-Finnish (FIN) AF: 0.280 AC: 2966 AN: 10578

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.241 AC: 16382 AN: 67958

Other (OTH) AF: 0.310 AC: 653 AN: 2106

Alfa AF: 0.285 Hom.: 2533

Bravo AF: 0.350

Asia WGS AF: 0.204 AC: 713 AN: 3478

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	-0.89
CADD	Benign	4.3
DANN	Benign	0.72
PhyloP100		0.35
Mutation Taster		=95/5	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs2075710; hg19: chr19-1106845;