chr1-151404881-T-C

Position:

• chr1-151404881-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The ENST00000271715.7(POGZ):​c.4154A>G​(p.His1385Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: POGZ ENST00000271715.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.89

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), POGZ. . Gene score misZ 3.5062 (greater than the threshold 3.09). Trascript score misZ 4.1346 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant 40, intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.16530293).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POGZ	NM_015100.4	c.4154A>G	p.His1385Arg	missense_variant	19/19	ENST00000271715.7	NP_055915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POGZ	ENST00000271715.7	c.4154A>G	p.His1385Arg	missense_variant	19/19	1	NM_015100.4	ENSP00000271715	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 09, 2017

The p.H1385R variant (also known as c.4154A>G), located in coding exon 18 of the POGZ gene, results from an A to G substitution at nucleotide position 4154. The histidine at codon 1385 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.022	.;T;.;.;.;.
Eigen	Benign	-0.060
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.17	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	.;N;.;.;.;.
MutationTaster	Benign	0.63	N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.74	N;N;N;N;N;N
REVEL	Benign	0.15
Sift	Uncertain	0.020	D;D;D;D;D;D
Sift4G	Benign	0.72	T;T;T;T;T;T
Polyphen		0.25	B;B;P;.;.;P
Vest4		0.32
MutPred		0.14		.;Gain of solvent accessibility (P = 0.0584);.;.;.;.;
MVP		0.64
MPC		0.50
ClinPred		0.46	T
GERP RS		5.3
Varity_R		0.13
gMVP		0.71

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: rs1557861908; hg19: chr1-151377357;