19-1106616-T-C

Position:

• chr19-1106616-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002085.5(GPX4):​c.*44T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.566 in 1,609,478 control chromosomes in the GnomAD database, including 259,442 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (27892 hom., cov: 33)
  • Exomes 𝑓: 0.56 (231550 hom.)
• Consequence: GPX4 NM_002085.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.13

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 19-1106616-T-C is Benign according to our data. Variant chr19-1106616-T-C is described in ClinVar as [Benign]. Clinvar id is 1268862.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.676 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPX4	NM_002085.5	c.*44T>C		3_prime_UTR_variant	7/7	ENST00000354171.13	NP_002076.2
GPX4	NM_001039847.3	c.660T>C	p.Leu220=	synonymous_variant	7/7		NP_001034936.1
GPX4	NM_001039848.4	c.*44T>C		3_prime_UTR_variant	7/7		NP_001034937.1
GPX4	NM_001367832.1	c.*44T>C		3_prime_UTR_variant	7/7		NP_001354761.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPX4	ENST00000354171.13	c.*44T>C		3_prime_UTR_variant	7/7	1	NM_002085.5	ENSP00000346103	P3

Frequencies

GnomAD3 genomes AF: 0.604 AC: 91764 AN: 151976 Hom.: 27860 Cov.: 33

Gnomad AFR AF: 0.683

Gnomad AMI AF: 0.785

Gnomad AMR AF: 0.630

Gnomad ASJ AF: 0.512

Gnomad EAS AF: 0.562

Gnomad SAS AF: 0.555

Gnomad FIN AF: 0.633

Gnomad MID AF: 0.544

Gnomad NFE AF: 0.556

Gnomad OTH AF: 0.570

GnomAD3 exomes AF: 0.578 AC: 139214 AN: 240876 Hom.: 40543 AF XY: 0.570 AC XY: 75064 AN XY: 131636

Gnomad AFR exome AF: 0.686

Gnomad AMR exome AF: 0.635

Gnomad ASJ exome AF: 0.516

Gnomad EAS exome AF: 0.567

Gnomad SAS exome AF: 0.550

Gnomad FIN exome AF: 0.626

Gnomad NFE exome AF: 0.554

Gnomad OTH exome AF: 0.544

GnomAD4 exome AF: 0.562 AC: 818333 AN: 1457384 Hom.: 231550 Cov.: 41 AF XY: 0.560 AC XY: 405760 AN XY: 724878

Gnomad4 AFR exome AF: 0.683

Gnomad4 AMR exome AF: 0.631

Gnomad4 ASJ exome AF: 0.516

Gnomad4 EAS exome AF: 0.613

Gnomad4 SAS exome AF: 0.542

Gnomad4 FIN exome AF: 0.622

Gnomad4 NFE exome AF: 0.554

Gnomad4 OTH exome AF: 0.555

GnomAD4 genome AF: 0.604 AC: 91844 AN: 152094 Hom.: 27892 Cov.: 33 AF XY: 0.606 AC XY: 45083 AN XY: 74336

Gnomad4 AFR AF: 0.683

Gnomad4 AMR AF: 0.630

Gnomad4 ASJ AF: 0.512

Gnomad4 EAS AF: 0.562

Gnomad4 SAS AF: 0.555

Gnomad4 FIN AF: 0.633

Gnomad4 NFE AF: 0.555

Gnomad4 OTH AF: 0.574

Alfa AF: 0.558 Hom.: 33946

Bravo AF: 0.606

Asia WGS AF: 0.599 AC: 2081 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	This variant is associated with the following publications: (PMID: 12490284, 21459128, 18400727) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.32
DANN	Benign	0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs713041; hg19: chr19-1106615; COSMIC: COSV62321056; COSMIC: COSV62321056;