chr3-49358324-G-A

Position:

• chr3-49358324-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.81

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]

ENSG00000290318 (HGNC:):

ACMG classification

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/exons	MANE	Protein	UniProt
GPX1	NM_000581.4	c.-46C>T		5_prime_UTR_variant	1/2	ENST00000419783.3	NP_000572.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPX1	ENST00000419783.3	c.-46C>T		5_prime_UTR_variant	1/2	1	NM_000581.4	ENSP00000407375.1
ENSG00000290318	ENST00000704381.1	c.465-577C>T		intron_variant				ENSP00000515884.1

Frequencies

GnomAD3 genomes AF: 0.281 AC: 42711 AN: 152034 Hom.: 6567 Cov.: 33

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

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.: 34 AF XY: 0.301 AC XY: 198941 AN XY: 660102

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.: 33 AF XY: 0.284 AC XY: 21107 AN XY: 74374

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

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	This variant is associated with the following publications: (PMID: 15331559) -

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

Other links and lift over

dbSNP: rs1800668; hg19: chr3-49395757; COSMIC: COSV104434407; COSMIC: COSV104434407;