19-56814359-A-ATCT

Position:

• chr19-56814359-A-ATCT

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP3 BP6_Moderate BS2

The NM_006210.3(PEG3):​c.4082_4083insAGA​(p.Glu1360dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00764 in 1,613,160 control chromosomes in the GnomAD database, including 53 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0065 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0078 (45 hom.)
• Consequence: PEG3 NM_006210.3 inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.278

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 Benign. Variant got -7 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_006210.3
• BP6: Variant 19-56814359-A-ATCT is Benign according to our data. Variant chr19-56814359-A-ATCT is described in ClinVar as [Likely_benign]. Clinvar id is 2650565.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEG3	NM_006210.3	c.4082_4083insAGA	p.Glu1360dup	inframe_insertion	10/10	ENST00000326441.15	NP_006201.1
ZIM2	NM_001387356.1	c.490+3386_490+3387insAGA		intron_variant		ENST00000629319.3	NP_001374285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEG3	ENST00000326441.15	c.4082_4083insAGA	p.Glu1360dup	inframe_insertion	10/10	1	NM_006210.3	ENSP00000326581	P1
ZIM2	ENST00000629319.3	c.490+3386_490+3387insAGA		intron_variant		5	NM_001387356.1	ENSP00000486502	A2
	ENST00000652504.1	n.844+4146_844+4148dup		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00646 AC: 983 AN: 152064 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0298

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00824

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00638 AC: 1586 AN: 248778 Hom.: 11 AF XY: 0.00635 AC XY: 854 AN XY: 134498

Gnomad AFR exome AF: 0.00130

Gnomad AMR exome AF: 0.00117

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000625

Gnomad FIN exome AF: 0.0272

Gnomad NFE exome AF: 0.00800

Gnomad OTH exome AF: 0.00495

GnomAD4 exome AF: 0.00777 AC: 11347 AN: 1460978 Hom.: 45 Cov.: 34 AF XY: 0.00748 AC XY: 5435 AN XY: 726826

Gnomad4 AFR exome AF: 0.00120

Gnomad4 AMR exome AF: 0.00123

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.000649

Gnomad4 FIN exome AF: 0.0244

Gnomad4 NFE exome AF: 0.00859

Gnomad4 OTH exome AF: 0.00550

GnomAD4 genome AF: 0.00646 AC: 983 AN: 152182 Hom.: 8 Cov.: 32 AF XY: 0.00675 AC XY: 502 AN XY: 74412

Gnomad4 AFR AF: 0.00169

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.0298

Gnomad4 NFE AF: 0.00824

Gnomad4 OTH AF: 0.00237

Bravo AF: 0.00430

EpiCase AF: 0.00671

EpiControl AF: 0.00601

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

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2023

ENSG00000286125: BS2; PEG3: BS2 -

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: rs572444111; hg19: chr19-57325727;