19-1106616-T-C

Variant names:

• chr19-1106616-T-C
• rs713041
• NM_002085.5:c.*44T>C

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.*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
• Publications: 154 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=-0.88).
• BP6: Variant 19-1106616-T-C is Benign according to our data. Variant chr19-1106616-T-C is described in ClinVar as Benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
GPX4	NM_002085.5	c.*44T>C		3_prime_UTR_variant	Exon 7 of 7	ENST00000354171.13	NP_002076.2
GPX4	NM_001039847.3	c.660T>C	p.Leu220Leu	synonymous_variant	Exon 7 of 7		NP_001034936.1
GPX4	NM_001039848.4	c.*44T>C		3_prime_UTR_variant	Exon 7 of 7		NP_001034937.1
GPX4	NM_001367832.1	c.*44T>C		3_prime_UTR_variant	Exon 7 of 7		NP_001354761.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPX4	ENST00000354171.13	c.*44T>C		3_prime_UTR_variant	Exon 7 of 7	1	NM_002085.5	ENSP00000346103.7

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

GnomAD2 exomes AF: 0.578 AC: 139214 AN: 240876 AF XY: 0.570

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 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

African (AFR) AF: 0.683 AC: 22787 AN: 33378

American (AMR) AF: 0.631 AC: 28004 AN: 44414

Ashkenazi Jewish (ASJ) AF: 0.516 AC: 13447 AN: 26066

East Asian (EAS) AF: 0.613 AC: 24234 AN: 39558

South Asian (SAS) AF: 0.542 AC: 46614 AN: 86024

European-Finnish (FIN) AF: 0.622 AC: 32445 AN: 52138

Middle Eastern (MID) AF: 0.480 AC: 2763 AN: 5754

European-Non Finnish (NFE) AF: 0.554 AC: 614629 AN: 1109870

Other (OTH) AF: 0.555 AC: 33410 AN: 60182

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

African (AFR) AF: 0.683 AC: 28319 AN: 41490

American (AMR) AF: 0.630 AC: 9632 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.512 AC: 1777 AN: 3468

East Asian (EAS) AF: 0.562 AC: 2907 AN: 5176

South Asian (SAS) AF: 0.555 AC: 2674 AN: 4822

European-Finnish (FIN) AF: 0.633 AC: 6702 AN: 10586

Middle Eastern (MID) AF: 0.537 AC: 158 AN: 294

European-Non Finnish (NFE) AF: 0.555 AC: 37745 AN: 67950

Other (OTH) AF: 0.574 AC: 1214 AN: 2114

Alfa AF: 0.570 Hom.: 60591

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

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 12490284, 21459128, 18400727) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.32
DANN	Benign	0.60
PhyloP100		-2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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

Other links and lift over

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