rs142860188

Variant names:

• chr1-151404946-A-C
• rs142860188
• NM_015100.4:c.4089T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015100.4(POGZ):​c.4089T>G​(p.His1363Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 1,614,140 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1363R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (5 hom.)
• Consequence: POGZ NM_015100.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 0.812
• Publications: 4 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042503476).
• BP6: Variant 1-151404946-A-C is Benign according to our data. Variant chr1-151404946-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00112 (170/152258) while in subpopulation AMR AF = 0.00222 (34/15290). AF 95% confidence interval is 0.00164. There are 1 homozygotes in GnomAd4. There are 75 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 170 AD gene.

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.4089T>G	p.His1363Gln	missense	Exon 19 of 19	NP_055915.2
	POGZ	NM_001410860.1		c.4110T>G	p.His1370Gln	missense	Exon 19 of 19	NP_001397789.1
	POGZ	NM_001194937.2		c.4062T>G	p.His1354Gln	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.4089T>G	p.His1363Gln	missense	Exon 19 of 19	ENSP00000271715.2
	POGZ	ENST00000392723.6	TSL:1	c.3930T>G	p.His1310Gln	missense	Exon 18 of 18	ENSP00000376484.1
	POGZ	ENST00000368863.6	TSL:1	c.3804T>G	p.His1268Gln	missense	Exon 17 of 17	ENSP00000357856.2

Frequencies

GnomAD3 genomes AF: 0.00112 AC: 170 AN: 152140 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00141

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00132 AC: 331 AN: 251476 AF XY: 0.00152

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00159

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00129 AC: 1893 AN: 1461882 Hom.: 5 Cov.: 36 AF XY: 0.00140 AC XY: 1018 AN XY: 727242

African (AFR) AF: 0.000179 AC: 6 AN: 33478

American (AMR) AF: 0.000671 AC: 30 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00241 AC: 63 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00313 AC: 270 AN: 86258

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53420

Middle Eastern (MID) AF: 0.00607 AC: 35 AN: 5768

European-Non Finnish (NFE) AF: 0.00123 AC: 1372 AN: 1112002

Other (OTH) AF: 0.00179 AC: 108 AN: 60396

GnomAD4 genome AF: 0.00112 AC: 170 AN: 152258 Hom.: 1 Cov.: 32 AF XY: 0.00101 AC XY: 75 AN XY: 74448

African (AFR) AF: 0.000217 AC: 9 AN: 41544

American (AMR) AF: 0.00222 AC: 34 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00404 AC: 14 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4824

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00141 AC: 96 AN: 68028

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00149 Hom.: 2

Bravo AF: 0.00114

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.00136 AC: 165

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00267

EpiControl AF: 0.00202

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Inborn genetic diseases (1)
-	-	1	Intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome (1)
-	-	1	POGZ-related disorder (1)
-	-	-	Autism spectrum disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	11
DANN	Benign	0.80
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.69	N
PhyloP100		0.81
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.30	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Sift4G	Benign	0.68	T
Polyphen		0.0	B
Vest4		0.063
MutPred		0.062		Gain of relative solvent accessibility (P = 0.0999)
MVP		0.15
MPC		0.30
ClinPred		0.0021	T
GERP RS		3.2
Varity_R		0.038
gMVP		0.22
Mutation Taster		=97/3	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: rs142860188; hg19: chr1-151377422; COSMIC: COSV105010115; COSMIC: COSV105010115;