Genetic Variant POGK:p.Met135Val (chr1-166848982-A-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_017542.5(POGK):c.403A>G(p.Met135Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,418 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

POGK
NM_017542.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.08

Publications

0 publications found

Variant links:

Genes affected

POGK (HGNC:18800): (pogo transposable element derived with KRAB domain) The exact function of the protein encoded by this gene is not known. However, this gene product contains a KRAB domain (which is involved in protein-protein interactions) at the N-terminus, and a transposase domain at the C-terminus, suggesting that it may belong to the family of DNA-mediated transposons in human. [provided by RefSeq, Jul 2008]

POGK links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.035972863).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POGK	NM_017542.5 link	c.403A>G	p.Met135Val	missense_variant	Exon 5 of 6	ENST00000367876.9	NP_060012.3	Q9P215A0A024R8Y1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
POGK	ENST00000367876.9 link	c.403A>G	p.Met135Val	missense_variant	Exon 5 of 6	1	NM_017542.5	ENSP00000356850.4	Q9P215
POGK	ENST00000367875.1 link	c.403A>G	p.Met135Val	missense_variant	Exon 5 of 5	5		ENSP00000356849.1	Q9P215
POGK	ENST00000449930.5 link	c.403A>G	p.Met135Val	missense_variant	Exon 5 of 5	2		ENSP00000404402.1	Q5TIJ2

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

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

GnomAD2 exomes

AF:

0.0000240

AC:

AN:

250468

AF XY:

0.0000296

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461250

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726928

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33442

American (AMR)

AF:

0.00

AC:

AN:

44604

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26066

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86144

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111768

Other (OTH)

AF:

0.0000166

AC:

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.536

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000197

Hom.:

Bravo

AF:

0.000102

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 12, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.403A>G (p.M135V) alteration is located in exon 5 (coding exon 4) of the POGK gene. This alteration results from a A to G substitution at nucleotide position 403, causing the methionine (M) at amino acid position 135 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.0010

(source)

DANN

Benign

0.30

DEOGEN2

Benign

0.014

T;T;T

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.51

T;.;T

M_CAP

Benign

0.0015

MetaRNN

Benign

0.036

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

.;N;N

PhyloP100

-2.1

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.28

N;N;N

REVEL

Benign

0.042

Sift

Benign

0.37

T;T;T

Sift4G

Benign

0.19

T;T;T

Polyphen

0.0

.;B;B

Vest4

0.052, 0.056

MVP

0.19

MPC

0.87

ClinPred

0.013

GERP RS

-9.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.027

gMVP

0.33

Mutation Taster

=89/11

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over