19-56814177-G-C

Variant names:

• chr19-56814177-G-C
• rs56237501
• NM_006210.3:c.4265C>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_006210.3(PEG3):​c.4265C>G​(p.Ala1422Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00646 in 1,614,070 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0037 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0067 (43 hom.)
• Consequence: PEG3 NM_006210.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.809
• Publications: 11 publications found

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]

ENSG00000286125 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005486667).
• BP6: Variant 19-56814177-G-C is Benign according to our data. Variant chr19-56814177-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 777915.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006210.3. 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
	PEG3	NM_006210.3	MANE Select	c.4265C>G	p.Ala1422Gly	missense	Exon 10 of 10	NP_006201.1	Q9GZU2-1
	ZIM2	NM_001387356.1	MANE Select	c.490+3569C>G		intron	N/A	NP_001374285.1	A0A8I5KWX0
	PEG3	NM_001369717.1		c.4271C>G	p.Ala1424Gly	missense	Exon 9 of 9	NP_001356646.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEG3	ENST00000326441.15	TSL:1 MANE Select	c.4265C>G	p.Ala1422Gly	missense	Exon 10 of 10	ENSP00000326581.7	Q9GZU2-1
	PEG3	ENST00000599534.5	TSL:1	c.4265C>G	p.Ala1422Gly	missense	Exon 7 of 7	ENSP00000472395.1	Q9GZU2-1
	PEG3	ENST00000599577.5	TSL:1	c.4265C>G	p.Ala1422Gly	missense	Exon 9 of 9	ENSP00000469486.1	Q9GZU2-1

Frequencies

GnomAD3 genomes AF: 0.00371 AC: 564 AN: 152132 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00353

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00617

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00417 AC: 1046 AN: 251082 AF XY: 0.00434

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00260

Gnomad ASJ exome AF: 0.00318

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000741

Gnomad NFE exome AF: 0.00642

Gnomad OTH exome AF: 0.00425

GnomAD4 exome AF: 0.00674 AC: 9855 AN: 1461820 Hom.: 43 Cov.: 34 AF XY: 0.00674 AC XY: 4898 AN XY: 727210

African (AFR) AF: 0.000836 AC: 28 AN: 33480

American (AMR) AF: 0.00300 AC: 134 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00367 AC: 96 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00443 AC: 382 AN: 86250

European-Finnish (FIN) AF: 0.000731 AC: 39 AN: 53362

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.00794 AC: 8829 AN: 1112008

Other (OTH) AF: 0.00563 AC: 340 AN: 60392

GnomAD4 genome AF: 0.00370 AC: 564 AN: 152250 Hom.: 5 Cov.: 32 AF XY: 0.00364 AC XY: 271 AN XY: 74440

African (AFR) AF: 0.00135 AC: 56 AN: 41560

American (AMR) AF: 0.00294 AC: 45 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00353 AC: 17 AN: 4810

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00617 AC: 420 AN: 68026

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.00616 Hom.: 2

Bravo AF: 0.00422

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00908 AC: 35

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00767 AC: 66

ExAC AF: 0.00413 AC: 501

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00676

EpiControl AF: 0.00646

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.81
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.070
Sift	Uncertain	0.017	D
Sift4G	Benign	0.078	T
Polyphen		0.80	P
Vest4		0.25
MVP		0.66
MPC		0.32
ClinPred		0.042	T
GERP RS		4.2
Varity_R		0.16
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: rs56237501; hg19: chr19-57325545; COSMIC: COSV99063477; COSMIC: COSV99063477;