chr19-1104778-G-C

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

Scores

2
7

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.0850
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 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
GPX4NM_002085.5 linkuse as main transcriptc.85-408G>C intron_variant ENST00000354171.13 NP_002076.2
GPX4NM_001039848.4 linkuse as main transcriptc.44G>C p.Arg15Pro missense_variant 1/7 NP_001034937.1
GPX4NM_001039847.3 linkuse as main transcriptc.85-408G>C intron_variant NP_001034936.1
GPX4NM_001367832.1 linkuse as main transcriptc.4-408G>C intron_variant NP_001354761.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GPX4ENST00000354171.13 linkuse as main transcriptc.85-408G>C intron_variant 1 NM_002085.5 ENSP00000346103 P3P36969-1

Frequencies

GnomAD3 genomes
AF:
0.000344
AC:
52
AN:
151258
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000194
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00204
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00318
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.00240
GnomAD4 exome
AF:
0.0000836
AC:
70
AN:
837552
Hom.:
0
Cov.:
30
AF XY:
0.0000852
AC XY:
33
AN XY:
387188
show subpopulations
Gnomad4 AFR exome
AF:
0.000126
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000786
Gnomad4 OTH exome
AF:
0.000292
GnomAD4 genome
AF:
0.000344
AC:
52
AN:
151366
Hom.:
0
Cov.:
33
AF XY:
0.000298
AC XY:
22
AN XY:
73944
show subpopulations
Gnomad4 AFR
AF:
0.000193
Gnomad4 AMR
AF:
0.00204
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00238
Bravo
AF:
0.000518
ExAC
AF:
0.000118
AC:
1

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 submitterclinical testingAmbry GeneticsDec 16, 2022The 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 06, 2022This 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

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.11
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
10
DANN
Benign
0.62
FATHMM_MKL
Benign
0.37
N
LIST_S2
Benign
0.46
.;T;.
MetaRNN
Benign
0.17
T;T;T
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.90
D
Sift4G
Pathogenic
0.0
D;D;D
Vest4
0.38
MVP
0.71
GERP RS
1.6
RBP_binding_hub_radar
1.1
RBP_regulation_power_radar
3.4

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: rs755894874; hg19: chr19-1104777; API