rs869320764

Positions:

• chr1-151405577-CCT-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The ENST00000271715.7(POGZ):​c.3456_3457del​(p.Glu1154ThrfsTer4) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: POGZ ENST00000271715.7 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• Conservation: PhyloP100: 4.31

Genes affected

POGZ (HGNC:18801): (pogo transposable element derived with ZNF domain) The protein encoded by this gene appears to be a zinc finger protein containing a transposase domain at the C-terminus. This protein was found to interact with the transcription factor SP1 in a yeast two-hybrid system. Alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Aug 2010]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 15 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-151405577-CCT-C is Pathogenic according to our data. Variant chr1-151405577-CCT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 224726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-151405577-CCT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POGZ	NM_015100.4	c.3456_3457del	p.Glu1154ThrfsTer4	frameshift_variant	19/19	ENST00000271715.7	NP_055915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POGZ	ENST00000271715.7	c.3456_3457del	p.Glu1154ThrfsTer4	frameshift_variant	19/19	1	NM_015100.4	ENSP00000271715	P3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome Pathogenic:8 Other:1

not provided, no classification provided	literature only	GeneReviews	-	Recurrent variant -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Oct 28, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 06, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 29, 2022	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Oct 31, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jun 29, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. Frameshift variant is predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000224726 / PMID: 26942287). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 21, 2024	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with White-Sutton syndrome (MIM#616364). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other protein truncating variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic, where a majority of individuals were de novo. A single case was reported to be maternally inherited, with limited clinical information provided for the mother (ClinVar, DECIPHER). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	POGZ: PS2, PVS1:Strong, PM2, PS4:Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 17, 2018	This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. This variant has been observed to be de novo in individuals affected with POGZ-related conditions (PMID: 26942287). ClinVar contains an entry for this variant (Variation ID: 224726). This sequence change results in a premature translational stop signal in the POGZ gene (p.Glu1154Thrfs*4). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 257 amino acids of the POGZ protein. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2022	Frameshift variant predicted to result in protein truncation, as the last 257 amino acids are replaced with 3 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26942287, 31981491, 31452935, 34215294, 31136090, 31782611) -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 28, 2019

The c.3456_3457delAG variant, located in coding exon 18 of the POGZ gene, results from a deletion of two nucleotides at nucleotide positions 3456 to 3457, causing a translational frameshift with a predicted alternate stop codon (p.E1154Tfs*4). This alteration was detected as de novo occurrences in two individuals with intellectual disability and developmental delay (Stessman HAF et al. Am. J. Hum. Genet., 2016 Mar;98:541-552). This amino acid position is highly conserved in available vertebrate species. This alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a likely pathogenic variant. -

POGZ-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 26, 2024

The POGZ c.3456_3457delAG variant is predicted to result in a frameshift and premature protein termination (p.Glu1154Thrfs*4). This variant was reported as a recurrent de novo event in individuals with White-Sutton syndrome (see, for example, Stessman et al. 2016. PubMed ID: 26942287; Assia Batzir et al. 2019. PubMed ID: 31782611). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in POGZ are expected to be pathogenic. This variant is interpreted as pathogenic. -

Neurodevelopmental disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Dec 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs869320764; hg19: chr1-151378053;