chr3-49358265-C-G

Variant names:

• chr3-49358265-C-G
• rs8179169
• NM_000581.4:c.14G>C

Variant summary

Our verdict is Benign. The variant received -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R5W) has been classified as Uncertain significance.

• 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
• Publications: 17 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 27 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000581.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPX1	NM_000581.4	MANE Select	c.14G>C	p.Arg5Pro	missense	Exon 1 of 2	NP_000572.2
	GPX1	NM_001329503.2		c.14G>C	p.Arg5Pro	missense	Exon 1 of 2	NP_001316432.1
	GPX1	NM_001329455.2		c.14G>C	p.Arg5Pro	missense	Exon 1 of 2	NP_001316384.1	A0A2R8Y6B6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPX1	ENST00000419783.3	TSL:1 MANE Select	c.14G>C	p.Arg5Pro	missense	Exon 1 of 2	ENSP00000407375.1	P07203-1
	ENSG00000290318	ENST00000704381.1		c.465-518G>C		intron	N/A	ENSP00000515884.1	A0A994J514
	GPX1	ENST00000703795.1		c.14G>C	p.Arg5Pro	missense	Exon 1 of 2	ENSP00000515480.1	A0A994J430

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

GnomAD2 exomes AF: 0.00264 AC: 351 AN: 132792 AF XY: 0.00250

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 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

African (AFR) AF: 0.0329 AC: 1031 AN: 31310

American (AMR) AF: 0.00292 AC: 102 AN: 34988

Ashkenazi Jewish (ASJ) AF: 0.00406 AC: 101 AN: 24902

East Asian (EAS) AF: 0.0000563 AC: 2 AN: 35512

South Asian (SAS) AF: 0.00748 AC: 586 AN: 78300

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47928

Middle Eastern (MID) AF: 0.00468 AC: 19 AN: 4058

European-Non Finnish (NFE) AF: 0.000291 AC: 313 AN: 1074892

Other (OTH) AF: 0.00360 AC: 207 AN: 57460

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

African (AFR) AF: 0.0321 AC: 1330 AN: 41462

American (AMR) AF: 0.00282 AC: 43 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5130

South Asian (SAS) AF: 0.00789 AC: 38 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 67974

Other (OTH) AF: 0.00805 AC: 17 AN: 2112

Alfa AF: 0.00168 Hom.: 2

Bravo AF: 0.0106

ExAC AF: 0.00149 AC: 87

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	GPX1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
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
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.63
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.043
Sift	Benign	0.056	T
Sift4G	Benign	0.062	T
Polyphen		0.0	B
Vest4		0.10
MVP		0.44
MPC		0.93
ClinPred		0.021	T
GERP RS		-5.3
PromoterAI		-0.029	Neutral
Varity_R		0.21
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs8179169; hg19: chr3-49395698;