19-56814215-A-AGCAGCCTCCACTTCTGGCTCG

Position:

• chr19-56814215-A-AGCAGCCTCCACTTCTGGCTCG

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM4 BP6_Moderate

The NM_006210.3(PEG3):​c.4226_4227insCGAGCCAGAAGTGGAGGCTGC​(p.Glu1412_Pro1418dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000717 in 151,938 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00072 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00081 (11 hom.)
  • Failed GnomAD Quality Control
• Consequence: PEG3 NM_006210.3 inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.10

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_006210.3.
• BP6: Variant 19-56814215-A-AGCAGCCTCCACTTCTGGCTCG is Benign according to our data. Variant chr19-56814215-A-AGCAGCCTCCACTTCTGGCTCG is described in ClinVar as [Likely_benign]. Clinvar id is 728809.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEG3	NM_006210.3	c.4226_4227insCGAGCCAGAAGTGGAGGCTGC	p.Glu1412_Pro1418dup	inframe_insertion	10/10	ENST00000326441.15	NP_006201.1
ZIM2	NM_001387356.1	c.490+3530_490+3531insCGAGCCAGAAGTGGAGGCTGC		intron_variant		ENST00000629319.3	NP_001374285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEG3	ENST00000326441.15	c.4226_4227insCGAGCCAGAAGTGGAGGCTGC	p.Glu1412_Pro1418dup	inframe_insertion	10/10	1	NM_006210.3	ENSP00000326581	P1
ZIM2	ENST00000629319.3	c.490+3530_490+3531insCGAGCCAGAAGTGGAGGCTGC		intron_variant		5	NM_001387356.1	ENSP00000486502	A2
	ENST00000652504.1	n.844+4008_844+4028dup		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000725 AC: 110 AN: 151822 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000774

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000854

Gnomad ASJ AF: 0.00116

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.00666

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000324

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00131 AC: 328 AN: 249794 Hom.: 3 AF XY: 0.00149 AC XY: 202 AN XY: 135200

Gnomad AFR exome AF: 0.000755

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.000700

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.00736

Gnomad FIN exome AF: 0.0000939

Gnomad NFE exome AF: 0.000398

Gnomad OTH exome AF: 0.00148

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000807 AC: 1179 AN: 1460304 Hom.: 11 Cov.: 34 AF XY: 0.000983 AC XY: 714 AN XY: 726504

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000805

Gnomad4 ASJ exome AF: 0.000921

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.00662

Gnomad4 FIN exome AF: 0.000151

Gnomad4 NFE exome AF: 0.000404

Gnomad4 OTH exome AF: 0.00111

GnomAD4 genome AF: 0.000717 AC: 109 AN: 151938 Hom.: 1 Cov.: 32 AF XY: 0.000794 AC XY: 59 AN XY: 74272

Gnomad4 AFR AF: 0.000772

Gnomad4 AMR AF: 0.000853

Gnomad4 ASJ AF: 0.00116

Gnomad4 EAS AF: 0.000582

Gnomad4 SAS AF: 0.00645

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000324

Gnomad4 OTH AF: 0.00190

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 28, 2017

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs748624205; hg19: chr19-57325583;