rs72996036

chr1-151411701-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BS1_Supporting BS2

The NM_015100.4(POGZ):c.1850G>A(p.Arg617Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,613,334 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: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: POGZ NM_015100.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.87

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 Likely_benign. Variant got -6 ACMG points.

• PP2: Missense variant where missense usually causes diseases, POGZ
• BP4: Computational evidence support a benign effect (MetaRNN=0.110709906).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000145 (22/151920) while in subpopulation AFR AF= 0.000411 (17/41400). AF 95% confidence interval is 0.000261. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POGZ	NM_015100.4	c.1850G>A	p.Arg617Gln	missense_variant	12/19	ENST00000271715.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POGZ	ENST00000271715.7	c.1850G>A	p.Arg617Gln	missense_variant	12/19	1	NM_015100.4	P3

Frequencies

GnomAD3 genomes AF: 0.000152 AC: 23 AN: 151812 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000436

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000960

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251376 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135870

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1461414 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727052

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.000145 AC: 22 AN: 151920 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74218

Gnomad4 AFR AF: 0.000411

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000950

Alfa AF: 0.000109 Hom.: 0

Bravo AF: 0.000125

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.000289 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 07, 2021	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 06, 2017

Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.23
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.11	T;T;T;T;T;T
MetaSVM	Benign	-0.52	T
MutationTaster	Benign	0.97	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.7	N;N;N;N;N;N
REVEL	Benign	0.22
Sift	Uncertain	0.027	D;D;D;D;D;D
Sift4G	Benign	0.069	T;T;T;T;T;T
Polyphen		1.0	D;D;D;.;.;D
Vest4		0.29
MVP		0.72
MPC		1.5
ClinPred		0.35	T
GERP RS		4.1
Varity_R		0.11
gMVP		0.72

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: rs72996036; hg19: chr1-151384177; COSMIC: COSV55033360; COSMIC: COSV55033360;