rs1860565

Variant names:

• chr19-56823654-G-A
• rs1860565
• NM_006210.3:c.420C>T

Variant summary

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

The NM_006210.3(PEG3):​c.420C>T​(p.Ser140Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.279 in 1,613,794 control chromosomes in the GnomAD database, including 66,191 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 0.22 (4538 hom., cov: 31)
  • Exomes 𝑓: 0.29 (61653 hom.)
• Consequence: PEG3 NM_006210.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.58

Genes affected

PEG3 (HGNC:8826): (paternally expressed 3) In human, ZIM2 and PEG3 are treated as two distinct genes though they share multiple 5' exons and a common promoter and both genes are paternally expressed (PMID:15203203). Alternative splicing events connect their shared 5' exons either with the remaining 4 exons unique to ZIM2, or with the remaining 2 exons unique to PEG3. In contrast, in other mammals ZIM2 does not undergo imprinting and, in mouse, cow, and likely other mammals as well, the ZIM2 and PEG3 genes do not share exons. Human PEG3 protein belongs to the Kruppel C2H2-type zinc finger protein family. PEG3 may play a role in cell proliferation and p53-mediated apoptosis. PEG3 has also shown tumor suppressor activity and tumorigenesis in glioma and ovarian cells. Alternative splicing of this PEG3 gene results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Sep 2009]

ZIM2 (HGNC:12875): (zinc finger imprinted 2) In human, ZIM2 and PEG3 (GeneID:5178) are two distinct genes that share a set of 5' exons and have a common promoter, and both genes are paternally expressed. Alternative splicing events connect the shared exons either with the remaining 4 exons unique to ZIM2, or with the remaining 2 exons unique to PEG3. This is in contrast to mouse and cow, where ZIM2 and PEG3 genes do not share exons in common, and the imprinting status of ZIM2 is also not conserved amongst mammals. Additional 5' alternatively spliced transcripts encoding the same protein have been found for the human ZIM2 gene. [provided by RefSeq, Oct 2010]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP7: Synonymous conserved (PhyloP=-1.58 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.314 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEG3	NM_006210.3	c.420C>T	p.Ser140Ser	synonymous_variant	Exon 5 of 10	ENST00000326441.15	NP_006201.1
ZIM2	NM_001387356.1	c.42C>T	p.Ser14Ser	synonymous_variant	Exon 5 of 13	ENST00000629319.3	NP_001374285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEG3	ENST00000326441.15	c.420C>T	p.Ser140Ser	synonymous_variant	Exon 5 of 10	1	NM_006210.3	ENSP00000326581.7
ZIM2	ENST00000629319.3	c.42C>T	p.Ser14Ser	synonymous_variant	Exon 5 of 13	5	NM_001387356.1	ENSP00000486502.2

Frequencies

GnomAD3 genomes AF: 0.224 AC: 34075 AN: 151878 Hom.: 4537 Cov.: 31

Gnomad AFR AF: 0.0815

Gnomad AMI AF: 0.204

Gnomad AMR AF: 0.321

Gnomad ASJ AF: 0.246

Gnomad EAS AF: 0.185

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.228

Gnomad MID AF: 0.242

Gnomad NFE AF: 0.285

Gnomad OTH AF: 0.234

GnomAD3 exomes AF: 0.283 AC: 70461 AN: 248990 Hom.: 11039 AF XY: 0.284 AC XY: 38279 AN XY: 134778

Gnomad AFR exome AF: 0.0755

Gnomad AMR exome AF: 0.436

Gnomad ASJ exome AF: 0.241

Gnomad EAS exome AF: 0.190

Gnomad SAS exome AF: 0.322

Gnomad FIN exome AF: 0.232

Gnomad NFE exome AF: 0.284

Gnomad OTH exome AF: 0.286

GnomAD4 exome AF: 0.285 AC: 416971 AN: 1461796 Hom.: 61653 Cov.: 38 AF XY: 0.286 AC XY: 207693 AN XY: 727210

Gnomad4 AFR exome AF: 0.0738

Gnomad4 AMR exome AF: 0.420

Gnomad4 ASJ exome AF: 0.238

Gnomad4 EAS exome AF: 0.197

Gnomad4 SAS exome AF: 0.322

Gnomad4 FIN exome AF: 0.237

Gnomad4 NFE exome AF: 0.291

Gnomad4 OTH exome AF: 0.272

GnomAD4 genome AF: 0.224 AC: 34073 AN: 151998 Hom.: 4538 Cov.: 31 AF XY: 0.223 AC XY: 16546 AN XY: 74246

Gnomad4 AFR AF: 0.0812

Gnomad4 AMR AF: 0.321

Gnomad4 ASJ AF: 0.246

Gnomad4 EAS AF: 0.185

Gnomad4 SAS AF: 0.300

Gnomad4 FIN AF: 0.228

Gnomad4 NFE AF: 0.285

Gnomad4 OTH AF: 0.232

Alfa AF: 0.275 Hom.: 14127

Bravo AF: 0.225

Asia WGS AF: 0.209 AC: 730 AN: 3478

EpiCase AF: 0.290

EpiControl AF: 0.282

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.39
DANN	Benign	0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1860565; hg19: chr19-57335022; COSMIC: COSV55634825; COSMIC: COSV55634825;