Genetic Variant EP300:c.5061+9C>T (chr22-41176537-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001429.4(EP300):c.5061+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0247 in 1,613,432 control chromosomes in the GnomAD database, including 650 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 57 hom., cov: 32)

Exomes 𝑓: 0.025 ( 593 hom. )

Consequence

EP300
NM_001429.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.656

Publications

5 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=-0.88).

BP6

Variant 22-41176537-C-T is Benign according to our data. Variant chr22-41176537-C-T is described in ClinVar as Benign. ClinVar VariationId is 158566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0208 (3171/152180) while in subpopulation SAS AF = 0.0338 (163/4818). AF 95% confidence interval is 0.0296. There are 57 homozygotes in GnomAd4. There are 1670 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 3171 AD gene.

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.5061+9C>T		intron	N/A	NP_001420.2	Q09472
	EP300	NM_001362843.2		c.4983+9C>T		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.5061+9C>T	intron	N/A	ENSP00000263253.7	Q09472
EP300	ENST00000916082.1		c.5091+9C>T	intron	N/A	ENSP00000586141.1
EP300	ENST00000715703.1		c.5061+9C>T	intron	N/A	ENSP00000520505.1	Q09472

Frequencies

GnomAD3 genomes

AF:

0.0208

AC:

3169

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00485

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.0180

Gnomad ASJ

AF:

0.0629

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0334

Gnomad FIN

AF:

0.0560

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0241

Gnomad OTH

AF:

0.0230

GnomAD2 exomes

AF:

0.0258

AC:

6445

AN:

249560

AF XY:

0.0274

show subpopulations

Gnomad AFR exome

AF:

0.00371

Gnomad AMR exome

AF:

0.0102

Gnomad ASJ exome

AF:

0.0616

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0588

Gnomad NFE exome

AF:

0.0253

Gnomad OTH exome

AF:

0.0302

GnomAD4 exome

AF:

0.0251

AC:

36731

AN:

1461252

Hom.:

593

Cov.:

AF XY:

0.0259

AC XY:

18819

AN XY:

726920

show subpopulations

African (AFR)

AF:

0.00436

AC:

146

AN:

33464

American (AMR)

AF:

0.0108

AC:

482

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.0599

AC:

1564

AN:

26132

East Asian (EAS)

AF:

0.000126

AC:

AN:

39698

South Asian (SAS)

AF:

0.0375

AC:

3234

AN:

86220

European-Finnish (FIN)

AF:

0.0549

AC:

2934

AN:

53396

Middle Eastern (MID)

AF:

0.0534

AC:

288

AN:

5390

European-Non Finnish (NFE)

AF:

0.0238

AC:

26475

AN:

1111922

Other (OTH)

AF:

0.0266

AC:

1603

AN:

60322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

2248

4497

6745

8994

11242

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1006

2012

3018

4024

5030

<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:

0.0208

AC:

3171

AN:

152180

Hom.:

Cov.:

AF XY:

0.0224

AC XY:

1670

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.00484

AC:

201

AN:

41534

American (AMR)

AF:

0.0179

AC:

274

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0629

AC:

218

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5168

South Asian (SAS)

AF:

0.0338

AC:

163

AN:

4818

European-Finnish (FIN)

AF:

0.0560

AC:

593

AN:

10586

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0241

AC:

1637

AN:

68012

Other (OTH)

AF:

0.0227

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

161

322

484

645

806

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.0243

Hom.:

Bravo

AF:

0.0178

Asia WGS

AF:

0.0160

AC:

AN:

3478

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

-0.88

CADD

Benign

0.66

(source)

DANN

Benign

0.77

PhyloP100

-0.66

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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