Genetic Variant POGZ:c.*269dupT (chr1-151404532-T-TA) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_015100.4(POGZ):c.*269dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0338 in 776,980 control chromosomes in the GnomAD database, including 3 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0022 ( 1 hom., cov: 32)

Exomes 𝑓: 0.041 ( 2 hom. )

Consequence

POGZ
NM_015100.4 3_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.191

Publications

0 publications found

Variant links:

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

POGZ links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00219 (311/142128) while in subpopulation AFR AF = 0.0039 (152/38928). AF 95% confidence interval is 0.0034. There are 1 homozygotes in GnomAd4. There are 143 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 311 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POGZ	NM_015100.4 link	c.*269dupT		3_prime_UTR_variant	Exon 19 of 19	ENST00000271715.7	NP_055915.2	Q7Z3K3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POGZ	ENST00000271715.7 link	c.*269dupT		3_prime_UTR_variant	Exon 19 of 19	1	NM_015100.4	ENSP00000271715.2		Q7Z3K3-1

Frequencies

GnomAD3 genomes

AF:

0.00218

AC:

310

AN:

142092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00389

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00246

Gnomad ASJ

AF:

0.000596

Gnomad EAS

AF:

0.00100

Gnomad SAS

AF:

0.00155

Gnomad FIN

AF:

0.00135

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00148

Gnomad OTH

AF:

0.00155

GnomAD4 exome

AF:

0.0409

AC:

25967

AN:

634852

Hom.:

Cov.:

AF XY:

0.0406

AC XY:

12116

AN XY:

298108

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0477

AC:

656

AN:

13758

American (AMR)

AF:

0.0584

AC:

302

AN:

5174

Ashkenazi Jewish (ASJ)

AF:

0.0506

AC:

375

AN:

7406

East Asian (EAS)

AF:

0.0596

AC:

669

AN:

11234

South Asian (SAS)

AF:

0.0406

AC:

503

AN:

12400

European-Finnish (FIN)

AF:

0.0575

AC:

418

AN:

7266

Middle Eastern (MID)

AF:

0.0457

AC:

AN:

1596

European-Non Finnish (NFE)

AF:

0.0396

AC:

21816

AN:

551278

Other (OTH)

AF:

0.0467

AC:

1155

AN:

24740

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.256

Heterozygous variant carriers

3572

7144

10716

14288

17860

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00219

AC:

311

AN:

142128

Hom.:

Cov.:

AF XY:

0.00208

AC XY:

143

AN XY:

68784

show subpopulations

African (AFR)

AF:

0.00390

AC:

152

AN:

38928

American (AMR)

AF:

0.00246

AC:

AN:

14256

Ashkenazi Jewish (ASJ)

AF:

0.000596

AC:

AN:

3358

East Asian (EAS)

AF:

0.00101

AC:

AN:

4968

South Asian (SAS)

AF:

0.00156

AC:

AN:

4492

European-Finnish (FIN)

AF:

0.00135

AC:

AN:

8176

Middle Eastern (MID)

AF:

0.00

AC:

AN:

278

European-Non Finnish (NFE)

AF:

0.00148

AC:

AN:

64832

Other (OTH)

AF:

0.00154

AC:

AN:

1952

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000546

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.19

Mutation Taster

=100/0

polymorphism

(source)

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

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chr1-151404532-T-TA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over