chr19-1104865-G-A
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1
The NM_002085.5(GPX4):c.85-321G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000611 in 1,195,712 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000057 ( 0 hom. )
Consequence
GPX4
NM_002085.5 intron
NM_002085.5 intron
Scores
3
5
Clinical Significance
Conservation
PhyloP100: 0.272
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 Benign. Variant got -7 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.02867186).
BP6
?
Variant 19-1104865-G-A is Benign according to our data. Variant chr19-1104865-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1028980.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
BS1
?
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000575 (60/1043540) while in subpopulation MID AF= 0.00524 (19/3626). AF 95% confidence interval is 0.00343. There are 0 homozygotes in gnomad4_exome. There are 37 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GPX4 | NM_002085.5 | c.85-321G>A | intron_variant | ENST00000354171.13 | |||
GPX4 | NM_001039848.4 | c.131G>A | p.Arg44Gln | missense_variant | 1/7 | ||
GPX4 | NM_001039847.3 | c.85-321G>A | intron_variant | ||||
GPX4 | NM_001367832.1 | c.4-321G>A | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GPX4 | ENST00000354171.13 | c.85-321G>A | intron_variant | 1 | NM_002085.5 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000855 AC: 13AN: 152056Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000147 AC: 17AN: 115738Hom.: 0 AF XY: 0.000138 AC XY: 9AN XY: 65160
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GnomAD4 exome AF: 0.0000575 AC: 60AN: 1043540Hom.: 0 Cov.: 30 AF XY: 0.0000741 AC XY: 37AN XY: 499000
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GnomAD4 genome ? AF: 0.0000854 AC: 13AN: 152172Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7AN XY: 74416
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Spondylometaphyseal dysplasia, Sedaghatian type Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 09, 2019 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Sep 30, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
FATHMM_MKL
Benign
N
MetaRNN
Benign
T;T;T
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
Sift4G
Uncertain
D;T;D
Vest4
0.20
MVP
GERP RS
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