chr19-1104053-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002085.5(GPX4):​c.10G>T​(p.Gly4Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000494 in 1,519,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000046 ( 0 hom. )

Consequence

GPX4
NM_002085.5 missense

Scores

1
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.651
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.07429844).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GPX4NM_002085.5 linkuse as main transcriptc.10G>T p.Gly4Cys missense_variant 1/7 ENST00000354171.13 NP_002076.2
GPX4NM_001039847.3 linkuse as main transcriptc.10G>T p.Gly4Cys missense_variant 1/7 NP_001034936.1
GPX4NM_001367832.1 linkuse as main transcript upstream_gene_variant NP_001354761.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GPX4ENST00000354171.13 linkuse as main transcriptc.10G>T p.Gly4Cys missense_variant 1/71 NM_002085.5 ENSP00000346103 P3P36969-1

Frequencies

GnomAD3 genomes
AF:
0.0000788
AC:
12
AN:
152254
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000344
AC:
4
AN:
116112
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
64316
show subpopulations
Gnomad AFR exome
AF:
0.000313
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000693
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000461
AC:
63
AN:
1367354
Hom.:
0
Cov.:
30
AF XY:
0.0000430
AC XY:
29
AN XY:
674556
show subpopulations
Gnomad4 AFR exome
AF:
0.0000346
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000129
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000541
Gnomad4 OTH exome
AF:
0.0000526
GnomAD4 genome
AF:
0.0000788
AC:
12
AN:
152254
Hom.:
0
Cov.:
34
AF XY:
0.0000672
AC XY:
5
AN XY:
74382
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000491
ExAC
AF:
0.0000910
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 19, 2022The c.10G>T (p.G4C) alteration is located in exon 1 (coding exon 1) of the GPX4 gene. This alteration results from a G to T substitution at nucleotide position 10, causing the glycine (G) at amino acid position 4 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.50
T
BayesDel_noAF
Benign
-0.64
CADD
Benign
18
DANN
Uncertain
0.98
DEOGEN2
Benign
0.0096
T;T;.
Eigen
Benign
-0.90
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.24
N
LIST_S2
Benign
0.46
T;T;.
MetaRNN
Benign
0.074
T;T;T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
0.0
.;N;.
MutationTaster
Benign
1.0
N;N
PROVEAN
Benign
-0.030
.;N;.
REVEL
Benign
0.074
Sift
Benign
0.034
.;D;.
Sift4G
Benign
0.068
T;.;.
Polyphen
0.67
.;P;.
Vest4
0.098
MutPred
0.36
Loss of methylation at R5 (P = 0.0428);Loss of methylation at R5 (P = 0.0428);Loss of methylation at R5 (P = 0.0428);
MVP
0.18
MPC
0.17
ClinPred
0.051
T
GERP RS
-0.67
Varity_R
0.14

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

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

Other links and lift over

dbSNP: rs772251077; hg19: chr19-1104052; API