Genetic Variant PGBD1:p.Thr263Ala (chr6-28297909-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_032507.4(PGBD1):c.787A>G(p.Thr263Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 1,518,054 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 0.000014 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0000058 ( 0 hom. )

Consequence

PGBD1
NM_032507.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.582

Publications

0 publications found

Variant links:

Genes affected

PGBD1 (HGNC:19398): (piggyBac transposable element derived 1) The piggyBac family of proteins, found in diverse animals, are transposases related to the transposase of the canonical piggyBac transposon from the moth, Trichoplusia ni. This family also includes genes in several genomes, including human, that appear to have been derived from the piggyBac transposons. This gene belongs to the subfamily of piggyBac transposable element derived (PGBD) genes. The PGBD proteins appear to be novel, with no obvious relationship to other transposases, or other known protein families. This gene product is specifically expressed in the brain, however, its exact function is not known. Alternative splicing results in multiple transcript variants encoding the same protein.[provided by RefSeq, May 2010]

PGBD1 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=0.042749077).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGBD1	NM_032507.4 link	c.787A>G	p.Thr263Ala	missense_variant	Exon 6 of 7	ENST00000682144.1	NP_115896.1	Q96JS3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PGBD1	ENST00000682144.1 link	c.787A>G	p.Thr263Ala	missense_variant	Exon 6 of 7		NM_032507.4	ENSP00000506997.1		Q96JS3
PGBD1	ENST00000259883.3 link	c.787A>G	p.Thr263Ala	missense_variant	Exon 6 of 7	1		ENSP00000259883.3		Q96JS3

Frequencies

GnomAD3 genomes

AF:

0.0000136

AC:

AN:

147556

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000406

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:

0.0000364

AC:

AN:

247074

AF XY:

0.0000224

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000498

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000584

AC:

AN:

1370498

Hom.:

Cov.:

AF XY:

0.00000293

AC XY:

AN XY:

682746

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31012

American (AMR)

AF:

0.00

AC:

AN:

41380

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23172

East Asian (EAS)

AF:

0.000232

AC:

AN:

34410

South Asian (SAS)

AF:

0.00

AC:

AN:

83818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49050

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5358

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1047028

Other (OTH)

AF:

0.00

AC:

AN:

55270

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000136

AC:

AN:

147556

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

71604

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

39838

American (AMR)

AF:

0.00

AC:

AN:

14502

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3436

East Asian (EAS)

AF:

0.000406

AC:

AN:

4926

South Asian (SAS)

AF:

0.00

AC:

AN:

4652

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

304

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67394

Other (OTH)

AF:

0.00

AC:

AN:

2026

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

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

Mar 30, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.787A>G (p.T263A) alteration is located in exon 6 (coding exon 5) of the PGBD1 gene. This alteration results from a A to G substitution at nucleotide position 787, causing the threonine (T) at amino acid position 263 to be replaced by an alanine (A). 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

0.075

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0093

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.44

M_CAP

Benign

0.0044

MetaRNN

Benign

0.043

MetaSVM

Benign

-0.89

MutationAssessor

Uncertain

2.1

PhyloP100

0.58

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.79

REVEL

Benign

0.022

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.050

Polyphen

0.39

Vest4

0.041

MutPred

0.22

Loss of phosphorylation at T263 (P = 0.0194);

MVP

0.21

ClinPred

0.21

GERP RS

3.3

Varity_R

0.15

gMVP

0.13

Mutation Taster

=98/2

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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6-28297909-A-G

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