3-49358265-C-G

Position:

• chr3-49358265-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000581.4(GPX1):​c.14G>C​(p.Arg5Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00249 in 1,541,366 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0097 (27 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (30 hom.)
• Consequence: GPX1 NM_000581.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.629

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021373928).
• BP6: Variant 3-49358265-C-G is Benign according to our data. Variant chr3-49358265-C-G is described in ClinVar as [Benign]. Clinvar id is 3056610.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00967 (1470/152016) while in subpopulation AFR AF= 0.0321 (1330/41462). AF 95% confidence interval is 0.0306. There are 27 homozygotes in gnomad4. There are 729 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPX1	NM_000581.4	c.14G>C	p.Arg5Pro	missense_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.14G>C	p.Arg5Pro	missense_variant	1/2	1	NM_000581.4	ENSP00000407375.1
ENSG00000290318	ENST00000704381.1	c.465-518G>C		intron_variant				ENSP00000515884.1

Frequencies

GnomAD3 genomes AF: 0.00966 AC: 1467 AN: 151898 Hom.: 27 Cov.: 33

Gnomad AFR AF: 0.0321

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00289

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00809

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00264 AC: 351 AN: 132792 Hom.: 4 AF XY: 0.00250 AC XY: 178 AN XY: 71208

Gnomad AFR exome AF: 0.0267

Gnomad AMR exome AF: 0.00226

Gnomad ASJ exome AF: 0.00200

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00520

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000236

Gnomad OTH exome AF: 0.00154

GnomAD4 exome AF: 0.00170 AC: 2361 AN: 1389350 Hom.: 30 Cov.: 37 AF XY: 0.00178 AC XY: 1215 AN XY: 684324

Gnomad4 AFR exome AF: 0.0329

Gnomad4 AMR exome AF: 0.00292

Gnomad4 ASJ exome AF: 0.00406

Gnomad4 EAS exome AF: 0.0000563

Gnomad4 SAS exome AF: 0.00748

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000291

Gnomad4 OTH exome AF: 0.00360

GnomAD4 genome AF: 0.00967 AC: 1470 AN: 152016 Hom.: 27 Cov.: 33 AF XY: 0.00981 AC XY: 729 AN XY: 74316

Gnomad4 AFR AF: 0.0321

Gnomad4 AMR AF: 0.00282

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00789

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.00805

Alfa AF: 0.00168 Hom.: 2

Bravo AF: 0.0106

ExAC AF: 0.00149 AC: 87

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

GPX1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 25, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	5.2
DANN	Benign	0.95
DEOGEN2	Benign	0.042	T;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.42	T;T;T;T
MetaRNN	Benign	0.0021	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.55	N;N;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.98	N;N;.;.
REVEL	Benign	0.043
Sift	Benign	0.056	T;D;.;.
Sift4G	Benign	0.062	T;.;T;.
Polyphen		0.0	B;.;.;.
Vest4		0.10
MVP		0.44
MPC		0.93
ClinPred		0.021	T
GERP RS		-5.3
Varity_R		0.21

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: rs8179169; hg19: chr3-49395698;