1-151404870-C-G

Variant names:

• chr1-151404870-C-G
• NM_015100.4:c.4165G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015100.4(POGZ):​c.4165G>C​(p.Glu1389Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,876 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: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: POGZ NM_015100.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.12
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38519788).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POGZ	NM_015100.4	c.4165G>C	p.Glu1389Gln	missense_variant	Exon 19 of 19	ENST00000271715.7	NP_055915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POGZ	ENST00000271715.7	c.4165G>C	p.Glu1389Gln	missense_variant	Exon 19 of 19	1	NM_015100.4	ENSP00000271715.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461876 Hom.: 0 Cov.: 36 AF XY: 0.00000275 AC XY: 2 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Oct 14, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4165G>C (p.E1389Q) alteration is located in exon 19 (coding exon 18) of the POGZ gene. This alteration results from a G to C substitution at nucleotide position 4165, causing the glutamic acid (E) at amino acid position 1389 to be replaced by a glutamine (Q). Based on data from the Genome Aggregation Database (gnomAD), the POGZ c.4165G>C alteration was not observed, with coverage at this position. This amino acid position is highly conserved in available vertebrate species. The p.E1389Q alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Jun 07, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

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

Apr 11, 2023

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.018	.;T;.;.;.;.
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.39	T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.81	.;L;.;.;.;.
PhyloP100		5.1
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.52	N;N;N;N;N;N
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		0.99	D;D;D;.;.;D
Vest4		0.52
MutPred		0.10		.;Gain of helix (P = 0.0225);.;.;.;.;
MVP		0.45
MPC		1.0
ClinPred		0.76	D
GERP RS		5.3
Varity_R		0.63
gMVP		0.58
Mutation Taster		=50/50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

hg19: chr1-151377346;