dbSNP rs2075710: GPX4:c.*274C>T (chr19-1106846-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.348

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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	Effect	MANE	Protein	UniProt
GPX4	NM_002085.5 link	c.*274C>T	downstream_gene_variant	ENST00000354171.13	NP_002076.2	P36969-1
GPX4	NM_001039848.4 link	c.*274C>T	downstream_gene_variant		NP_001034937.1	Q6PI42
GPX4	NM_001039847.3 link	c.*206C>T	downstream_gene_variant		NP_001034936.1	P36969
GPX4	NM_001367832.1 link	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 link	c.*274C>T		downstream_gene_variant		1	NM_002085.5	ENSP00000346103.7		P36969-1

Frequencies

GnomAD3 genomes

AF:

0.336

AC:

51071

AN:

151972

Hom.:

9970

Cov.:

show subpopulations

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

show subpopulations

Gnomad4 AFR exome

AF:

0.534

Gnomad4 AMR exome

AF:

0.375

Gnomad4 ASJ exome

AF:

0.294

Gnomad4 EAS exome

AF:

0.172

Gnomad4 SAS exome

AF:

0.234

Gnomad4 FIN exome

AF:

0.262

Gnomad4 NFE exome

AF:

0.245

Gnomad4 OTH exome

AF:

0.259

GnomAD4 genome

AF:

0.336

AC:

51124

AN:

152090

Hom.:

9983

Cov.:

AF XY:

0.335

AC XY:

24936

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.543

Gnomad4 AMR

AF:

0.360

Gnomad4 ASJ

AF:

0.288

Gnomad4 EAS

AF:

0.128

Gnomad4 SAS

AF:

0.221

Gnomad4 FIN

AF:

0.280

Gnomad4 NFE

AF:

0.241

Gnomad4 OTH

AF:

0.310

Alfa

AF:

0.288

Hom.:

1423

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

LINK: link

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

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over