rs6446261

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000581.4(GPX1):ā€‹c.580G>Cā€‹(p.Ala194Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A194T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)
Exomes š‘“: 6.8e-7 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

GPX1
NM_000581.4 missense

Scores

2
15

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.873
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.18467388).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GPX1NM_000581.4 linkc.580G>C p.Ala194Pro missense_variant Exon 2 of 2 ENST00000419783.3 NP_000572.2 P07203-1Q7L4Q3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GPX1ENST00000419783.3 linkc.580G>C p.Ala194Pro missense_variant Exon 2 of 2 1 NM_000581.4 ENSP00000407375.1 P07203-1
ENSG00000290318ENST00000704381 linkc.*300G>C 3_prime_UTR_variant Exon 6 of 6 ENSP00000515884.1 A0A994J514

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.00000408
AC:
1
AN:
245164
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
133840
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
6.85e-7
AC:
1
AN:
1460244
Hom.:
0
Cov.:
34
AF XY:
0.00
AC XY:
0
AN XY:
726272
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31
ExAC
AF:
0.00000831
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.50
CADD
Benign
20
DANN
Uncertain
0.98
DEOGEN2
Benign
0.065
T;.;.
Eigen
Benign
-0.32
Eigen_PC
Benign
-0.25
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Benign
0.83
T;T;D
MetaRNN
Benign
0.18
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
2.0
M;.;.
PrimateAI
Benign
0.29
T
PROVEAN
Benign
-1.4
N;.;.
REVEL
Benign
0.092
Sift
Benign
0.28
T;.;.
Sift4G
Benign
0.23
T;T;.
Polyphen
0.0
B;.;.
Vest4
0.32
MutPred
0.44
Gain of disorder (P = 0.0189);.;.;
MVP
0.36
MPC
0.88
ClinPred
0.080
T
GERP RS
3.3
Varity_R
0.29

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: rs6446261; hg19: chr3-49394853; API