NM_006210.3:c.4634A>G

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006210.3(PEG3):c.4634A>G(p.Tyr1545Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,614,132 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

PEG3
NM_006210.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.453

Variant links:

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]

PEG3 links:

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]

ZIM2 links:

ENSG00000286125 (HGNC:):

ENSG00000286125 links:

PEG3-AS1 (HGNC:35127): (PEG3 antisense RNA 1) This gene is located in the paternally expressed gene 3 (PEG3) imprinted region on chromosome 19. The corresponding transcript in mouse is imprinted and regulates expression of the mouse Peg3 gene. [provided by RefSeq, Sep 2016]

PEG3-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08562487).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEG3	NM_006210.3 link	c.4634A>G	p.Tyr1545Cys	missense_variant	Exon 10 of 10	ENST00000326441.15	NP_006201.1	Q9GZU2-1
ZIM2	NM_001387356.1 link	c.490+3938A>G		intron_variant	Intron 9 of 12	ENST00000629319.3	NP_001374285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEG3	ENST00000326441.15 link	c.4634A>G	p.Tyr1545Cys	missense_variant	Exon 10 of 10	1	NM_006210.3	ENSP00000326581.7		Q9GZU2-1
ZIM2	ENST00000629319.3 link	c.490+3938A>G		intron_variant	Intron 9 of 12	5	NM_001387356.1	ENSP00000486502.2		A0A8I5KWX0

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251206

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135828

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000151

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000900

Hom.:

Bravo

AF:

0.000348

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 17, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4634A>G (p.Y1545C) alteration is located in exon 10 (coding exon 7) of the PEG3 gene. This alteration results from a A to G substitution at nucleotide position 4634, causing the tyrosine (Y) at amino acid position 1545 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.33

T;.;.;.;.;.;.;.;.;.;.;T;T

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.12

LIST_S2

Uncertain

0.86

.;.;.;.;.;.;.;.;D;D;D;.;D

M_CAP

Benign

0.0064

MetaRNN

Benign

0.086

T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.90

L;.;.;.;.;.;.;.;.;.;.;L;L

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-2.7

D;.;.;.;.;.;.;.;.;.;.;.;.

REVEL

Benign

0.11

Sift

Uncertain

0.017

D;.;.;.;.;.;.;.;.;.;.;.;.

Sift4G

Benign

0.11

T;.;.;.;.;.;.;.;.;T;T;T;T

Polyphen

0.88

P;.;.;.;.;.;.;.;.;.;.;P;P

Vest4

0.40

MutPred

0.63

Gain of helix (P = 0.0225);.;.;.;.;.;.;.;.;.;.;Gain of helix (P = 0.0225);Gain of helix (P = 0.0225);

MVP

0.57

MPC

0.060

ClinPred

0.38

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.15

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over