1-151404940-C-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_015100.4(POGZ):c.4095G>T(p.Glu1365Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00297 in 1,614,152 control chromosomes in the GnomAD database, including 139 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (84 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (55 hom.)
• Consequence: POGZ NM_015100.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.14

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 Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, POGZ
• BP4: Computational evidence support a benign effect (MetaRNN=0.0015791357).
• BP6: Variant 1-151404940-C-A is Benign according to our data. Variant chr1-151404940-C-A is described in ClinVar as [Benign]. Clinvar id is 587845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0554 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POGZ	NM_015100.4	c.4095G>T	p.Glu1365Asp	missense_variant	19/19	ENST00000271715.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POGZ	ENST00000271715.7	c.4095G>T	p.Glu1365Asp	missense_variant	19/19	1	NM_015100.4	P3

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2508 AN: 152144 Hom.: 84 Cov.: 32

Gnomad AFR AF: 0.0576

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00635

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00955

GnomAD3 exomes AF: 0.00437 AC: 1099 AN: 251472 Hom.: 30 AF XY: 0.00323 AC XY: 439 AN XY: 135914

Gnomad AFR exome AF: 0.0609

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000527

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00156 AC: 2282 AN: 1461890 Hom.: 55 Cov.: 36 AF XY: 0.00128 AC XY: 934 AN XY: 727248

Gnomad4 AFR exome AF: 0.0569

Gnomad4 AMR exome AF: 0.00271

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000279

Gnomad4 OTH exome AF: 0.00343

GnomAD4 genome AF: 0.0165 AC: 2506 AN: 152262 Hom.: 84 Cov.: 32 AF XY: 0.0163 AC XY: 1215 AN XY: 74468

Gnomad4 AFR AF: 0.0573

Gnomad4 AMR AF: 0.00634

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00945

Alfa AF: 0.00552 Hom.: 13

Bravo AF: 0.0188

ESP6500AA AF: 0.0599 AC: 264

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00539 AC: 655

Asia WGS AF: 0.00144 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	17
Dann	Uncertain	0.98
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.78	T;T;T;T;T;T
MetaRNN	Benign	0.0016	T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	0.99	N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.030	N;N;N;N;N;N
REVEL	Benign	0.090
Sift	Benign	0.23	T;T;T;T;T;T
Sift4G	Benign	0.84	T;T;T;T;T;T
Polyphen		0.011	B;B;B;.;.;B
Vest4		0.12
MutPred		0.030		.;Loss of glycosylation at S1367 (P = 0.1514);.;.;.;.;
MVP		0.29
MPC		0.35
ClinPred		0.011	T
GERP RS		4.1
Varity_R		0.060
gMVP		0.29

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: rs35198305; hg19: chr1-151377416;