Genetic Variant EP300:c.2131+18T>A (chr22-41146834-T-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001429.4(EP300):c.2131+18T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0351 in 1,605,846 control chromosomes in the GnomAD database, including 1,304 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.026 ( 88 hom., cov: 32)

Exomes 𝑓: 0.036 ( 1216 hom. )

Consequence

EP300
NM_001429.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.0920

Publications

1 publications found

Variant links:

Genes affected

EP300 (HGNC:3373): (E1A binding protein p300) This gene encodes the adenovirus E1A-associated cellular p300 transcriptional co-activator protein. It functions as histone acetyltransferase that regulates transcription via chromatin remodeling and is important in the processes of cell proliferation and differentiation. It mediates cAMP-gene regulation by binding specifically to phosphorylated CREB protein. This gene has also been identified as a co-activator of HIF1A (hypoxia-inducible factor 1 alpha), and thus plays a role in the stimulation of hypoxia-induced genes such as VEGF. Defects in this gene are a cause of Rubinstein-Taybi syndrome and may also play a role in epithelial cancer. [provided by RefSeq, Jul 2008]

EP300 links:

EP300-AS1 (HGNC:50504): (EP300 antisense RNA 1)

EP300-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 22-41146834-T-A is Benign according to our data. Variant chr22-41146834-T-A is described in ClinVar as Benign. ClinVar VariationId is 93733.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0776 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001429.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EP300	NM_001429.4	MANE Select	c.2131+18T>A		intron	N/A	NP_001420.2	Q09472
	EP300	NM_001362843.2		c.2054-1003T>A		intron	N/A	NP_001349772.1	A0A669KB12

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
EP300	ENST00000263253.9	TSL:1 MANE Select	c.2131+18T>A	intron	N/A	ENSP00000263253.7	Q09472
EP300	ENST00000916082.1		c.2131+18T>A	intron	N/A	ENSP00000586141.1
EP300	ENST00000715703.1		c.2131+18T>A	intron	N/A	ENSP00000520505.1	Q09472

Frequencies

GnomAD3 genomes

AF:

0.0259

AC:

3923

AN:

151682

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00619

Gnomad AMI

AF:

0.0351

Gnomad AMR

AF:

0.0205

Gnomad ASJ

AF:

0.0217

Gnomad EAS

AF:

0.00270

Gnomad SAS

AF:

0.0837

Gnomad FIN

AF:

0.0377

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0347

Gnomad OTH

AF:

0.0345

GnomAD2 exomes

AF:

0.0347

AC:

8483

AN:

244412

AF XY:

0.0392

show subpopulations

Gnomad AFR exome

AF:

0.00567

Gnomad AMR exome

AF:

0.0147

Gnomad ASJ exome

AF:

0.0226

Gnomad EAS exome

AF:

0.00247

Gnomad FIN exome

AF:

0.0352

Gnomad NFE exome

AF:

0.0364

Gnomad OTH exome

AF:

0.0337

GnomAD4 exome

AF:

0.0360

AC:

52367

AN:

1454046

Hom.:

1216

Cov.:

AF XY:

0.0379

AC XY:

27456

AN XY:

723646

show subpopulations

African (AFR)

AF:

0.00581

AC:

192

AN:

33062

American (AMR)

AF:

0.0153

AC:

684

AN:

44652

Ashkenazi Jewish (ASJ)

AF:

0.0236

AC:

615

AN:

26080

East Asian (EAS)

AF:

0.00147

AC:

AN:

39364

South Asian (SAS)

AF:

0.0875

AC:

7497

AN:

85702

European-Finnish (FIN)

AF:

0.0389

AC:

2059

AN:

52966

Middle Eastern (MID)

AF:

0.0516

AC:

294

AN:

5700

European-Non Finnish (NFE)

AF:

0.0352

AC:

38956

AN:

1106432

Other (OTH)

AF:

0.0335

AC:

2012

AN:

60088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

2348

4696

7045

9393

11741

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1460

2920

4380

5840

7300

<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:

0.0258

AC:

3922

AN:

151800

Hom.:

Cov.:

AF XY:

0.0267

AC XY:

1981

AN XY:

74214

show subpopulations

African (AFR)

AF:

0.00617

AC:

256

AN:

41470

American (AMR)

AF:

0.0205

AC:

313

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0217

AC:

AN:

3454

East Asian (EAS)

AF:

0.00271

AC:

AN:

5172

South Asian (SAS)

AF:

0.0844

AC:

407

AN:

4824

European-Finnish (FIN)

AF:

0.0377

AC:

397

AN:

10538

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0347

AC:

2349

AN:

67750

Other (OTH)

AF:

0.0337

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

176

352

527

703

879

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<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:

0.0287

Hom.:

Bravo

AF:

0.0225

Asia WGS

AF:

0.0220

AC:

AN:

3476

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Rubinstein-Taybi syndrome due to EP300 haploinsufficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.26

(source)

DANN

Benign

0.32

PhyloP100

-0.092

Mutation Taster

=100/0

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over