1-151406046-G-C

Variant names:

• chr1-151406046-G-C
• rs1553212545
• NM_015100.4:c.2989C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015100.4(POGZ):​c.2989C>G​(p.Arg997Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,614,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: POGZ NM_015100.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.52
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11885589).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015100.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POGZ	NM_015100.4	MANE Select	c.2989C>G	p.Arg997Gly	missense	Exon 19 of 19	NP_055915.2
	POGZ	NM_001410860.1		c.3010C>G	p.Arg1004Gly	missense	Exon 19 of 19	NP_001397789.1
	POGZ	NM_001194937.2		c.2962C>G	p.Arg988Gly	missense	Exon 19 of 19	NP_001181866.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POGZ	ENST00000271715.7	TSL:1 MANE Select	c.2989C>G	p.Arg997Gly	missense	Exon 19 of 19	ENSP00000271715.2
	POGZ	ENST00000392723.6	TSL:1	c.2830C>G	p.Arg944Gly	missense	Exon 18 of 18	ENSP00000376484.1
	POGZ	ENST00000368863.6	TSL:1	c.2704C>G	p.Arg902Gly	missense	Exon 17 of 17	ENSP00000357856.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461886 Hom.: 0 Cov.: 35 AF XY: 0.00000275 AC XY: 2 AN XY: 727246

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: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112006

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

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74336

African (AFR) AF: 0.0000241 AC: 1 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5208

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 08, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R997G variant (also known as c.2989C>G), located in coding exon 18 of the POGZ gene, results from a C to G substitution at nucleotide position 2989. The arginine at codon 997 is replaced by glycine, an amino acid with dissimilar 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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.0091
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.5
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.15
Sift	Benign	0.18	T
Sift4G	Benign	0.51	T
Polyphen		0.76	P
Vest4		0.31
MutPred		0.24		Loss of helix (P = 0.0237)
MVP		0.43
MPC		0.75
ClinPred		0.42	T
GERP RS		5.8
Varity_R		0.12
gMVP		0.86
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs1553212545; hg19: chr1-151378522;