chr1-151411741-C-A

Variant names:

• chr1-151411741-C-A
• rs1135401798
• NM_015100.4:c.1810G>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1 PM2 PP3_Moderate PP5_Moderate

The NM_015100.4(POGZ):​c.1810G>T​(p.Glu604*) variant causes a stop gained change involving the alteration of a conserved nucleotide. 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: POGZ NM_015100.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.85
• 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Illumina

ACMG classification

Our verdict: Pathogenic. The variant received 14 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
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 1-151411741-C-A is Pathogenic according to our data. Variant chr1-151411741-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 431126.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POGZ	NM_015100.4	MANE Select	c.1810G>T	p.Glu604*	stop_gained	Exon 12 of 19	NP_055915.2
	POGZ	NM_001410860.1		c.1831G>T	p.Glu611*	stop_gained	Exon 12 of 19	NP_001397789.1	A0A8V8TQ67
	POGZ	NM_001194937.2		c.1783G>T	p.Glu595*	stop_gained	Exon 12 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.1810G>T	p.Glu604*	stop_gained	Exon 12 of 19	ENSP00000271715.2	Q7Z3K3-1
	POGZ	ENST00000392723.6	TSL:1	c.1651G>T	p.Glu551*	stop_gained	Exon 11 of 18	ENSP00000376484.1	Q7Z3K3-2
	POGZ	ENST00000368863.6	TSL:1	c.1525G>T	p.Glu509*	stop_gained	Exon 10 of 17	ENSP00000357856.2	Q7Z3K3-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	56
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		7.8
Vest4		0.59
GERP RS		5.0
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.92		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.92		Position offset: -3
DS_AL_spliceai		0.85		Position offset: 30

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1135401798; hg19: chr1-151384217;