rs1553226286

chr1-151428348-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_015100.4(POGZ):c.634G>A(p.Val212Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: POGZ NM_015100.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 5.55

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, POGZ
• BP4: Computational evidence support a benign effect (MetaRNN=0.37819222).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POGZ	NM_015100.4	c.634G>A	p.Val212Met	missense_variant	6/19	ENST00000271715.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POGZ	ENST00000271715.7	c.634G>A	p.Val212Met	missense_variant	6/19	1	NM_015100.4	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461816 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 21, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing;provider interpretation	Geisinger Autism and Developmental Medicine Institute, Geisinger Health System	Aug 30, 2017	This 12 year old male with autism spectrum disorder, anxiety, learning disorder, motor stereotypies, esotropia, myopia, enuresis, and dysmorphic features (particularly midface hypoplasia and a generally flat face) was found to carry a missense variant in the POGZ gene. Inheritance is unknown, as a paternal sample is unavailable. The patient's father is reported to have autistic features. Intellectual disability, autism, dysmorphic features, and vision issues have been seen in individuals with pathogenic variants in POGZ. The p.Val212Met variant is absent from population databases. Computational prediction models are inconsistent. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 08, 2019

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.38	T;T;T;T;T;T
MetaSVM	Uncertain	0.098	D
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;N
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.59	N;N;N;N;N;N
REVEL	Uncertain	0.33
Sift	Uncertain	0.0090	D;D;D;D;D;D
Sift4G	Benign	0.11	T;T;D;D;D;T
Polyphen		0.99	D;D;D;.;.;D
Vest4		0.57
MutPred		0.082		.;Gain of glycosylation at P214 (P = 0.1005);.;Gain of glycosylation at P214 (P = 0.1005);.;.;
MVP		0.67
MPC		1.8
ClinPred		0.82	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.76

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: rs1553226286; hg19: chr1-151400824;