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rs1050450

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000581.4(GPX1):c.599C>T(p.Pro200Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.3 in 1,607,594 control chromosomes in the GnomAD database, including 76,163 homozygotes. 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 Benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 7172 hom., cov: 30)
Exomes 𝑓: 0.30 ( 68991 hom. )

Consequence

GPX1
NM_000581.4 missense

Scores

2
15

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.39
Variant links:
Genes affected
GPX1 (HGNC:4553): (glutathione peroxidase 1) The protein encoded by this gene belongs to the glutathione peroxidase family, members of which catalyze the reduction of organic hydroperoxides and hydrogen peroxide (H2O2) by glutathione, and thereby protect cells against oxidative damage. Other studies indicate that H2O2 is also essential for growth-factor mediated signal transduction, mitochondrial function, and maintenance of thiol redox-balance; therefore, by limiting H2O2 accumulation, glutathione peroxidases are also involved in modulating these processes. Several isozymes of this gene family exist in vertebrates, which vary in cellular location and substrate specificity. This isozyme is the most abundant, is ubiquitously expressed and localized in the cytoplasm, and whose preferred substrate is hydrogen peroxide. It 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. This gene contains an in-frame GCG trinucleotide repeat in the coding region, and three alleles with 4, 5 or 6 repeats have been found in the human population. The allele with 4 GCG repeats has been significantly associated with breast cancer risk in premenopausal women. Alternatively spliced transcript variants have been found for this gene. Pseudogenes of this locus have been identified on chromosomes X and 21. [provided by RefSeq, Aug 2017]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=5.634427E-4).
BP6
Variant 3-49357401-G-A is Benign according to our data. Variant chr3-49357401-G-A is described in ClinVar as [Benign]. Clinvar id is 16082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-49357401-G-A is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.303 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GPX1NM_000581.4 linkuse as main transcriptc.599C>T p.Pro200Leu missense_variant 2/2 ENST00000419783.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GPX1ENST00000419783.3 linkuse as main transcriptc.599C>T p.Pro200Leu missense_variant 2/21 NM_000581.4 P3P07203-1

Frequencies

GnomAD3 genomes
AF:
0.297
AC:
45043
AN:
151596
Hom.:
7165
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.292
Gnomad AMI
AF:
0.198
Gnomad AMR
AF:
0.220
Gnomad ASJ
AF:
0.461
Gnomad EAS
AF:
0.0578
Gnomad SAS
AF:
0.226
Gnomad FIN
AF:
0.472
Gnomad MID
AF:
0.326
Gnomad NFE
AF:
0.306
Gnomad OTH
AF:
0.299
GnomAD3 exomes
AF:
0.280
AC:
68269
AN:
244032
Hom.:
11117
AF XY:
0.283
AC XY:
37740
AN XY:
133308
show subpopulations
Gnomad AFR exome
AF:
0.291
Gnomad AMR exome
AF:
0.156
Gnomad ASJ exome
AF:
0.455
Gnomad EAS exome
AF:
0.0559
Gnomad SAS exome
AF:
0.237
Gnomad FIN exome
AF:
0.465
Gnomad NFE exome
AF:
0.312
Gnomad OTH exome
AF:
0.302
GnomAD4 exome
AF:
0.300
AC:
436513
AN:
1455880
Hom.:
68991
Cov.:
34
AF XY:
0.299
AC XY:
215897
AN XY:
723240
show subpopulations
Gnomad4 AFR exome
AF:
0.294
Gnomad4 AMR exome
AF:
0.164
Gnomad4 ASJ exome
AF:
0.455
Gnomad4 EAS exome
AF:
0.0631
Gnomad4 SAS exome
AF:
0.243
Gnomad4 FIN exome
AF:
0.454
Gnomad4 NFE exome
AF:
0.307
Gnomad4 OTH exome
AF:
0.304
GnomAD4 genome
AF:
0.297
AC:
45072
AN:
151714
Hom.:
7172
Cov.:
30
AF XY:
0.299
AC XY:
22165
AN XY:
74098
show subpopulations
Gnomad4 AFR
AF:
0.292
Gnomad4 AMR
AF:
0.219
Gnomad4 ASJ
AF:
0.461
Gnomad4 EAS
AF:
0.0581
Gnomad4 SAS
AF:
0.226
Gnomad4 FIN
AF:
0.472
Gnomad4 NFE
AF:
0.306
Gnomad4 OTH
AF:
0.297
Alfa
AF:
0.322
Hom.:
2756
Bravo
AF:
0.277
ESP6500AA
AF:
0.273
AC:
983
ESP6500EA
AF:
0.294
AC:
2330
ExAC
AF:
0.276
AC:
33009
Asia WGS
AF:
0.149
AC:
524
AN:
3478
EpiCase
AF:
0.317
EpiControl
AF:
0.312

ClinVar

Significance: Benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

GLUTATHIONE PEROXIDASE POLYMORPHISM Benign:1
Benign, no assertion criteria providedliterature onlyOMIMJan 01, 1999- -
Gluthathione peroxidase deficiency Benign:1
Benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsAug 16, 2021- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxNov 12, 2018This variant is associated with the following publications: (PMID: 27592002, 30256368, 22139612, 21636625, 18563616, 29411539, 11103801, 19826042, 22888637, 20178852, 21165435, 16287877, 20441054, 16956821, 21993316, 19415410, 23073788, 15331559, 16945136, 25047527) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.68
T
BayesDel_noAF
Benign
-0.61
Cadd
Benign
20
Dann
Uncertain
0.98
DEOGEN2
Benign
0.039
T;.;.
Eigen
Benign
-0.61
Eigen_PC
Benign
-0.60
FATHMM_MKL
Benign
0.22
N
LIST_S2
Benign
0.68
T;T;T
MetaRNN
Benign
0.00056
T;T;T
MetaSVM
Benign
-0.90
T
MutationAssessor
Benign
0.34
N;.;.
MutationTaster
Benign
0.079
P;P
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-1.1
N;.;.
REVEL
Benign
0.083
Sift
Benign
0.036
D;.;.
Sift4G
Uncertain
0.060
T;T;.
Polyphen
0.0
B;.;.
Vest4
0.094
MPC
0.79
ClinPred
0.012
T
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.072

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: rs1050450; hg19: chr3-49394834; COSMIC: COSV69042017; COSMIC: COSV69042017; API