dbSNP rs1800668: GPX1:c.-46C>T (chr3-49358324-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

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

The NM_000581.4(GPX1):c.-46C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.3 in 1,500,264 control chromosomes in the GnomAD database, including 70,818 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.28 ( 6569 hom., cov: 33)

Exomes 𝑓: 0.30 ( 64249 hom. )

Consequence

GPX1
NM_000581.4 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.81

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]

GPX1 links:

ENSG00000290318 (HGNC:):

ENSG00000290318 links:

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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 (BayesDel_noAF=-0.7).

BP6

Variant 3-49358324-G-A is Benign according to our data. Variant chr3-49358324-G-A is described in ClinVar as [Benign]. Clinvar id is 1252486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
GPX1	NM_000581.4 link	c.-46C>T		5_prime_UTR_variant	Exon 1 of 2	ENST00000419783.3	NP_000572.2	P07203-1Q7L4Q3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPX1	ENST00000419783.3 link	c.-46C>T		5_prime_UTR_variant	Exon 1 of 2	1	NM_000581.4	ENSP00000407375.1		P07203-1
ENSG00000290318	ENST00000704381.1 link	c.465-577C>T		intron_variant	Intron 5 of 5			ENSP00000515884.1		A0A994J514

Frequencies

GnomAD3 genomes

AF:

0.281

AC:

42711

AN:

152034

Hom.:

6567

Cov.:

show subpopulations

Gnomad AFR

AF:

0.235

Gnomad AMI

AF:

0.199

Gnomad AMR

AF:

0.216

Gnomad ASJ

AF:

0.461

Gnomad EAS

AF:

0.0582

Gnomad SAS

AF:

0.226

Gnomad FIN

AF:

0.472

Gnomad MID

AF:

0.316

Gnomad NFE

AF:

0.306

Gnomad OTH

AF:

0.287

GnomAD3 exomes

AF:

0.295

AC:

33864

AN:

114888

Hom.:

5635

AF XY:

0.295

AC XY:

18138

AN XY:

61550

show subpopulations

Gnomad AFR exome

AF:

0.239

Gnomad AMR exome

AF:

0.191

Gnomad ASJ exome

AF:

0.494

Gnomad EAS exome

AF:

0.0572

Gnomad SAS exome

AF:

0.258

Gnomad FIN exome

AF:

0.479

Gnomad NFE exome

AF:

0.329

Gnomad OTH exome

AF:

0.310

GnomAD4 exome

AF:

0.302

AC:

407576

AN:

1348112

Hom.:

64249

Cov.:

AF XY:

0.301

AC XY:

198941

AN XY:

660102

show subpopulations

Gnomad4 AFR exome

AF:

0.240

Gnomad4 AMR exome

AF:

0.191

Gnomad4 ASJ exome

AF:

0.462

Gnomad4 EAS exome

AF:

0.0631

Gnomad4 SAS exome

AF:

0.248

Gnomad4 FIN exome

AF:

0.457

Gnomad4 NFE exome

AF:

0.308

Gnomad4 OTH exome

AF:

0.302

GnomAD4 genome

AF:

0.281

AC:

42726

AN:

152152

Hom.:

6569

Cov.:

AF XY:

0.284

AC XY:

21107

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.235

Gnomad4 AMR

AF:

0.216

Gnomad4 ASJ

AF:

0.461

Gnomad4 EAS

AF:

0.0586

Gnomad4 SAS

AF:

0.226

Gnomad4 FIN

AF:

0.472

Gnomad4 NFE

AF:

0.306

Gnomad4 OTH

AF:

0.285

Alfa

AF:

0.283

Hom.:

2162

Bravo

AF:

0.258

Asia WGS

AF:

0.143

AC:

502

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 15331559) -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

4.6

DANN

Benign

0.67

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over