NM_002085.5:c.477-134G>T
Variant names:
Variant summary
Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_002085.5(GPX4):c.477-134G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0497 in 825,770 control chromosomes in the GnomAD database, including 1,675 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.048 ( 317 hom., cov: 25)
Exomes 𝑓: 0.050 ( 1358 hom. )
Consequence
GPX4
NM_002085.5 intron
NM_002085.5 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.721
Publications
3 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 typeInheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet
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ACMG classification
Classification was made for transcript
Our verdict: Benign. The variant received -20 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.8).
BP6
Variant 19-1106108-G-T is Benign according to our data. Variant chr19-1106108-G-T is described in CliVar as Likely_benign. Clinvar id is 1321762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1106108-G-T is described in CliVar as Likely_benign. Clinvar id is 1321762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1106108-G-T is described in CliVar as Likely_benign. Clinvar id is 1321762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1106108-G-T is described in CliVar as Likely_benign. Clinvar id is 1321762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1106108-G-T is described in CliVar as Likely_benign. Clinvar id is 1321762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1106108-G-T is described in CliVar as Likely_benign. Clinvar id is 1321762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1106108-G-T is described in CliVar as Likely_benign. Clinvar id is 1321762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1106108-G-T is described in CliVar as Likely_benign. Clinvar id is 1321762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1106108-G-T is described in CliVar as Likely_benign. Clinvar id is 1321762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1106108-G-T is described in CliVar as Likely_benign. Clinvar id is 1321762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1106108-G-T is described in CliVar as Likely_benign. Clinvar id is 1321762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1106108-G-T is described in CliVar as Likely_benign. Clinvar id is 1321762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1106108-G-T is described in CliVar as Likely_benign. Clinvar id is 1321762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1106108-G-T is described in CliVar as Likely_benign. Clinvar id is 1321762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1106108-G-T is described in CliVar as Likely_benign. Clinvar id is 1321762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.157 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GPX4 | NM_002085.5 | c.477-134G>T | intron_variant | Intron 4 of 6 | ENST00000354171.13 | NP_002076.2 | ||
GPX4 | NM_001039848.4 | c.588-134G>T | intron_variant | Intron 4 of 6 | NP_001034937.1 | |||
GPX4 | NM_001039847.3 | c.477-134G>T | intron_variant | Intron 4 of 6 | NP_001034936.1 | |||
GPX4 | NM_001367832.1 | c.396-134G>T | intron_variant | Intron 4 of 6 | NP_001354761.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0477 AC: 7063AN: 148042Hom.: 318 Cov.: 25 show subpopulations
GnomAD3 genomes
AF:
AC:
7063
AN:
148042
Hom.:
Cov.:
25
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome AF: 0.0501 AC: 33972AN: 677614Hom.: 1358 Cov.: 9 AF XY: 0.0493 AC XY: 17251AN XY: 349686 show subpopulations
GnomAD4 exome
AF:
AC:
33972
AN:
677614
Hom.:
Cov.:
9
AF XY:
AC XY:
17251
AN XY:
349686
show subpopulations
African (AFR)
AF:
AC:
167
AN:
17260
American (AMR)
AF:
AC:
4834
AN:
21704
Ashkenazi Jewish (ASJ)
AF:
AC:
787
AN:
15086
East Asian (EAS)
AF:
AC:
32
AN:
33056
South Asian (SAS)
AF:
AC:
2176
AN:
53400
European-Finnish (FIN)
AF:
AC:
1022
AN:
31254
Middle Eastern (MID)
AF:
AC:
90
AN:
2406
European-Non Finnish (NFE)
AF:
AC:
23205
AN:
469916
Other (OTH)
AF:
AC:
1659
AN:
33532
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.513
Heterozygous variant carriers
0
1627
3254
4882
6509
8136
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Exome Hom
Variant carriers
0
528
1056
1584
2112
2640
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome AF: 0.0476 AC: 7059AN: 148156Hom.: 317 Cov.: 25 AF XY: 0.0481 AC XY: 3475AN XY: 72226 show subpopulations
GnomAD4 genome
AF:
AC:
7059
AN:
148156
Hom.:
Cov.:
25
AF XY:
AC XY:
3475
AN XY:
72226
show subpopulations
African (AFR)
AF:
AC:
488
AN:
40330
American (AMR)
AF:
AC:
2388
AN:
14698
Ashkenazi Jewish (ASJ)
AF:
AC:
169
AN:
3424
East Asian (EAS)
AF:
AC:
8
AN:
4974
South Asian (SAS)
AF:
AC:
155
AN:
4582
European-Finnish (FIN)
AF:
AC:
294
AN:
10318
Middle Eastern (MID)
AF:
AC:
13
AN:
286
European-Non Finnish (NFE)
AF:
AC:
3392
AN:
66612
Other (OTH)
AF:
AC:
118
AN:
2050
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.510
Heterozygous variant carriers
0
291
582
872
1163
1454
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Genome Het
Genome Hom
Variant carriers
0
72
144
216
288
360
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
Hom.:
Asia WGS
AF:
AC:
89
AN:
3478
ClinVar
Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:2
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:not provided
- -
May 12, 2021
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
DANN
Benign
PhyloP100
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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