rs864321671

Variant names:

• chr1-151408150-CAGAG-C
• rs864321671
• NM_015100.4:c.2321_2324delCTCT

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_015100.4(POGZ):​c.2321_2324delCTCT​(p.Ser774CysfsTer16) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 30)
• Consequence: POGZ NM_015100.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.04
• Publications: 2 publications found

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]

POGZ Gene-Disease associations (from GenCC):

• intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Illumina, G2P, Orphanet, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-151408150-CAGAG-C is Pathogenic according to our data. Variant chr1-151408150-CAGAG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 218146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015100.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POGZ	NM_015100.4	MANE Select	c.2321_2324delCTCT	p.Ser774CysfsTer16	frameshift	Exon 15 of 19	NP_055915.2
	POGZ	NM_001410860.1		c.2342_2345delCTCT	p.Ser781CysfsTer16	frameshift	Exon 15 of 19	NP_001397789.1
	POGZ	NM_001194937.2		c.2294_2297delCTCT	p.Ser765CysfsTer16	frameshift	Exon 15 of 19	NP_001181866.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POGZ	ENST00000271715.7	TSL:1 MANE Select	c.2321_2324delCTCT	p.Ser774CysfsTer16	frameshift	Exon 15 of 19	ENSP00000271715.2
	POGZ	ENST00000392723.6	TSL:1	c.2162_2165delCTCT	p.Ser721CysfsTer16	frameshift	Exon 14 of 18	ENSP00000376484.1
	POGZ	ENST00000368863.6	TSL:1	c.2036_2039delCTCT	p.Ser679CysfsTer16	frameshift	Exon 13 of 17	ENSP00000357856.2

Frequencies

GnomAD3 genomes Cov.: 30

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

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome (2)
1	-	-	not provided (1)
1	-	-	Smith-Magenis Syndrome-like (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.0
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs864321671; hg19: chr1-151380626;