1-151406941-A-AG

Variant names:

• chr1-151406941-A-AG
• rs796052221
• NM_015100.4:c.2514dupC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_015100.4(POGZ):​c.2514dupC​(p.Ser839LeufsTer25) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: POGZ NM_015100.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.185
• 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 12 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 1-151406941-A-AG is Pathogenic according to our data. Variant chr1-151406941-A-AG is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 207801.Status of the report is criteria_provided_single_submitter, 1 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.2514dupC	p.Ser839LeufsTer25	frameshift	Exon 17 of 19	NP_055915.2
	POGZ	NM_001410860.1		c.2535dupC	p.Ser846LeufsTer25	frameshift	Exon 17 of 19	NP_001397789.1
	POGZ	NM_001194937.2		c.2487dupC	p.Ser830LeufsTer25	frameshift	Exon 17 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.2514dupC	p.Ser839LeufsTer25	frameshift	Exon 17 of 19	ENSP00000271715.2
	POGZ	ENST00000392723.6	TSL:1	c.2355dupC	p.Ser786LeufsTer25	frameshift	Exon 16 of 18	ENSP00000376484.1
	POGZ	ENST00000368863.6	TSL:1	c.2229dupC	p.Ser744LeufsTer25	frameshift	Exon 15 of 17	ENSP00000357856.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Mar 23, 2015

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.2514dupC: p.Ser839LeufsX25 in exon 17 in the POGZ Gene (NM_015100.3). The normal sequence with the base that is duplicated in braces is: ACCC{C}TCTC. The c.2514dupC variant in the POGZ gene causes a frameshift starting with codon Serine 839, changes this amino acid to a Leucine residue and creates a premature Stop codon at position 25 of the new reading frame, denoted p.Ser839LeufsX25. This variant is predicted to cause loss of normal protein function through protein truncation. The c.2514dupC variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The c.2514dupC variant is a good candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.18
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: rs796052221; hg19: chr1-151379417;