19-56814075-G-A

Position:

chr19-56814075-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006210.3(PEG3):c.4367C>T(p.Ala1456Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 1,614,018 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.010 ( 33 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 28 hom. )

Consequence

PEG3
NM_006210.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.00600

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002305895).

BP6

Variant 19-56814075-G-A is Benign according to our data. Variant chr19-56814075-G-A is described in ClinVar as [Benign]. Clinvar id is 769057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0105 (1597/152128) while in subpopulation AFR AF= 0.0358 (1486/41520). AF 95% confidence interval is 0.0343. There are 33 homozygotes in gnomad4. There are 734 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEG3	NM_006210.3 linkuse as main transcript	c.4367C>T	p.Ala1456Val	missense_variant	10/10	ENST00000326441.15	NP_006201.1
ZIM2	NM_001387356.1 linkuse as main transcript	c.490+3671C>T		intron_variant		ENST00000629319.3	NP_001374285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEG3	ENST00000326441.15 linkuse as main transcript	c.4367C>T	p.Ala1456Val	missense_variant	10/10	1	NM_006210.3	ENSP00000326581	P1	Q9GZU2-1
ZIM2	ENST00000629319.3 linkuse as main transcript	c.490+3671C>T		intron_variant		5	NM_001387356.1	ENSP00000486502	A2
	ENST00000652504.1 linkuse as main transcript	n.844+3847G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0105

AC:

1593

AN:

152010

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0358

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00531

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00719

GnomAD3 exomes

AF:

0.00283

AC:

710

AN:

251192

Hom.:

AF XY:

0.00193

AC XY:

262

AN XY:

135744

show subpopulations

Gnomad AFR exome

AF:

0.0391

Gnomad AMR exome

AF:

0.00159

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.00104

AC:

1522

AN:

1461890

Hom.:

Cov.:

AF XY:

0.000868

AC XY:

631

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0362

Gnomad4 AMR exome

AF:

0.00208

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000504

Gnomad4 OTH exome

AF:

0.00238

GnomAD4 genome

AF:

0.0105

AC:

1597

AN:

152128

Hom.:

Cov.:

AF XY:

0.00987

AC XY:

734

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.0358

Gnomad4 AMR

AF:

0.00530

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00712

Alfa

AF:

0.00205

Hom.:

Bravo

AF:

0.0119

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0340

AC:

150

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00354

AC:

430

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 06, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

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

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.079

LIST_S2

Benign

0.78

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

MetaRNN

Benign

0.0023

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

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.5

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

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.7

N;.;.;.;.;.;.;.;.;.;.;.;.

REVEL

Benign

0.072

Sift

Benign

0.039

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

Sift4G

Benign

0.12

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

Polyphen

0.0050

B;.;.;.;.;.;.;.;.;.;.;B;B

Vest4

0.12

MVP

0.39

MPC

0.067

ClinPred

0.0037

GERP RS

1.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.059

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