rs3750105

chr7-94665370-C-Achr7-94665370-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001172437.2(PEG10):c.2043C>A(p.Ile681=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 718,718 control chromosomes in the GnomAD database, including 9,001 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.12 (1402 hom., cov: 32)
  • Exomes 𝑓: 0.16 (7599 hom.)
• Consequence: PEG10 NM_001172437.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.239

Genes affected

PEG10 (HGNC:14005): (paternally expressed 10) This is a paternally expressed imprinted gene that is thought to have been derived from the Ty3/Gypsy family of retrotransposons. It contains two overlapping open reading frames, RF1 and RF2, and expresses two proteins: a shorter, gag-like protein (with a CCHC-type zinc finger domain) from RF1; and a longer, gag/pol-like fusion protein (with an additional aspartic protease motif) from RF1/RF2 by -1 translational frameshifting (-1 FS). While -1 FS has been observed in RNA viruses and transposons in both prokaryotes and eukaryotes, this gene represents the first example of -1 FS in a eukaryotic cellular gene. This gene is highly conserved across mammalian species and retains the heptanucleotide (GGGAAAC) and pseudoknot elements required for -1 FS. It is expressed in adult and embryonic tissues (most notably in placenta) and reported to have a role in cell proliferation, differentiation and apoptosis. Overexpression of this gene has been associated with several malignancies, such as hepatocellular carcinoma and B-cell lymphocytic leukemia. Knockout mice lacking this gene showed early embryonic lethality with placental defects, indicating the importance of this gene in embryonic development. Additional isoforms resulting from alternatively spliced transcript variants, and use of upstream non-AUG (CUG) start codon have been reported for this gene. [provided by RefSeq, Oct 2014]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP7: Synonymous conserved (PhyloP=-0.239 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.232 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEG10	NM_001172437.2	c.2043C>A	p.Ile681=	synonymous_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEG10	ENST00000612748.1	c.2040C>A	p.Ile680=	synonymous_variant	3/3	5		A2

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17973 AN: 151988 Hom.: 1397 Cov.: 32

Gnomad AFR AF: 0.0261

Gnomad AMI AF: 0.153

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.246

Gnomad FIN AF: 0.213

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.116

GnomAD3 exomes AF: 0.162 AC: 25526 AN: 157788 Hom.: 2327 AF XY: 0.166 AC XY: 13826 AN XY: 83356

Gnomad AFR exome AF: 0.0198

Gnomad AMR exome AF: 0.166

Gnomad ASJ exome AF: 0.134

Gnomad EAS exome AF: 0.224

Gnomad SAS exome AF: 0.236

Gnomad FIN exome AF: 0.210

Gnomad NFE exome AF: 0.132

Gnomad OTH exome AF: 0.150

GnomAD4 exome AF: 0.155 AC: 88087 AN: 566612 Hom.: 7599 Cov.: 0 AF XY: 0.160 AC XY: 48821 AN XY: 305638

Gnomad4 AFR exome AF: 0.0246

Gnomad4 AMR exome AF: 0.162

Gnomad4 ASJ exome AF: 0.134

Gnomad4 EAS exome AF: 0.233

Gnomad4 SAS exome AF: 0.235

Gnomad4 FIN exome AF: 0.205

Gnomad4 NFE exome AF: 0.133

Gnomad4 OTH exome AF: 0.136

GnomAD4 genome AF: 0.118 AC: 17965 AN: 152106 Hom.: 1402 Cov.: 32 AF XY: 0.125 AC XY: 9311 AN XY: 74326

Gnomad4 AFR AF: 0.0260

Gnomad4 AMR AF: 0.152

Gnomad4 ASJ AF: 0.142

Gnomad4 EAS AF: 0.228

Gnomad4 SAS AF: 0.244

Gnomad4 FIN AF: 0.213

Gnomad4 NFE AF: 0.133

Gnomad4 OTH AF: 0.115

Alfa AF: 0.134 Hom.: 3246

Bravo AF: 0.109

Asia WGS AF: 0.194 AC: 677 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
Cadd	Benign	7.8
Dann	Benign	0.85

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: rs3750105; hg19: chr7-94294682; COSMIC: COSV71788320; COSMIC: COSV71788320;