NM_015100.4:c.2590C>T

Variant names:

• chr1-151406445-G-A
• rs756659230
• NM_015100.4:c.2590C>T

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.2590C>T​(p.Arg864*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: POGZ NM_015100.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.84
• Publications: 1 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: Illumina, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 18 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 81 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-151406445-G-A is Pathogenic according to our data. Variant chr1-151406445-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 224723.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POGZ	NM_015100.4	MANE Select	c.2590C>T	p.Arg864*	stop_gained	Exon 19 of 19	NP_055915.2
	POGZ	NM_001410860.1		c.2611C>T	p.Arg871*	stop_gained	Exon 19 of 19	NP_001397789.1	A0A8V8TQ67
	POGZ	NM_001194937.2		c.2563C>T	p.Arg855*	stop_gained	Exon 19 of 19	NP_001181866.1	Q7Z3K3-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POGZ	ENST00000271715.7	TSL:1 MANE Select	c.2590C>T	p.Arg864*	stop_gained	Exon 19 of 19	ENSP00000271715.2	Q7Z3K3-1
	POGZ	ENST00000392723.6	TSL:1	c.2431C>T	p.Arg811*	stop_gained	Exon 18 of 18	ENSP00000376484.1	Q7Z3K3-2
	POGZ	ENST00000368863.6	TSL:1	c.2305C>T	p.Arg769*	stop_gained	Exon 17 of 17	ENSP00000357856.2	Q7Z3K3-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely 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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		3.8
Vest4		0.26
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs756659230; hg19: chr1-151378921;