chr19-1104778-G-C
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Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting
The NM_002085.5(GPX4):c.85-408G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000123 in 988,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00034 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000084 ( 0 hom. )
Consequence
GPX4
NM_002085.5 intron
NM_002085.5 intron
Scores
2
7
Clinical Significance
Conservation
PhyloP100: 0.0850
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.16870055).
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000344 (52/151366) while in subpopulation AMR AF= 0.00204 (31/15208). AF 95% confidence interval is 0.00148. There are 0 homozygotes in gnomad4. There are 22 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GPX4 | NM_002085.5 | c.85-408G>C | intron_variant | ENST00000354171.13 | NP_002076.2 | |||
GPX4 | NM_001039848.4 | c.44G>C | p.Arg15Pro | missense_variant | 1/7 | NP_001034937.1 | ||
GPX4 | NM_001039847.3 | c.85-408G>C | intron_variant | NP_001034936.1 | ||||
GPX4 | NM_001367832.1 | c.4-408G>C | intron_variant | NP_001354761.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GPX4 | ENST00000354171.13 | c.85-408G>C | intron_variant | 1 | NM_002085.5 | ENSP00000346103 | P3 |
Frequencies
GnomAD3 genomes AF: 0.000344 AC: 52AN: 151258Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.0000836 AC: 70AN: 837552Hom.: 0 Cov.: 30 AF XY: 0.0000852 AC XY: 33AN XY: 387188
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GnomAD4 genome AF: 0.000344 AC: 52AN: 151366Hom.: 0 Cov.: 33 AF XY: 0.000298 AC XY: 22AN XY: 73944
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 16, 2022 | The c.44G>C (p.R15P) alteration is located in exon 1 (coding exon 1) of the GPX4 gene. This alteration results from a G to C substitution at nucleotide position 44, causing the arginine (R) at amino acid position 15 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 06, 2022 | This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 15 of the GPX4 protein (p.Arg15Pro). This variant is present in population databases (rs755894874, gnomAD 0.3%). This variant has not been reported in the literature in individuals affected with GPX4-related conditions. ClinVar contains an entry for this variant (Variation ID: 1523088). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
.;T;.
MetaRNN
Benign
T;T;T
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
Sift4G
Pathogenic
D;D;D
Vest4
0.38
MVP
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at