3-49357889-C-G

Variant names:

• chr3-49357889-C-G
• rs2047871383
• NM_000581.4:c.252+138G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001329502.2(GPX1):​c.253-1G>C variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000735 in 1,360,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: GPX1 NM_001329502.2 splice_acceptor, intron
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -0.576
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001329502.2. 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.252+138G>C		intron	N/A	NP_000572.2
	GPX1	NM_201397.3		c.*93G>C		3_prime_UTR	Exon 1 of 1	NP_958799.1	P07203-2
	GPX1	NM_001329503.2		c.253-123G>C		intron	N/A	NP_001316432.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPX1	ENST00000419783.3	TSL:1 MANE Select	c.252+138G>C		intron	N/A	ENSP00000407375.1	P07203-1
	ENSG00000290318	ENST00000704381.1		c.465-142G>C		intron	N/A	ENSP00000515884.1	A0A994J514
	GPX1	ENST00000419349.3	TSL:6	c.*93G>C		3_prime_UTR	Exon 1 of 1	ENSP00000391316.1	P07203-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.35e-7 AC: 1 AN: 1360436 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 667104

African (AFR) AF: 0.00 AC: 0 AN: 30574

American (AMR) AF: 0.0000337 AC: 1 AN: 29650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20326

East Asian (EAS) AF: 0.00 AC: 0 AN: 38482

South Asian (SAS) AF: 0.00 AC: 0 AN: 72870

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5206

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1065612

Other (OTH) AF: 0.00 AC: 0 AN: 56124

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

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
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.5
DANN	Benign	0.40
PhyloP100		-0.58
PromoterAI		-0.45	Neutral
Mutation Taster		=100/0	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: rs2047871383; hg19: chr3-49395322;