rs146242251

Variant names:

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.1519A>G(p.Ser507Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000781 in 1,614,146 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00089 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00077 ( 6 hom. )

Consequence

EP300
NM_001429.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: 3.08

Publications

19 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 Gene-Disease associations (from GenCC):

Rubinstein-Taybi syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: Illumina
Rubinstein-Taybi syndrome due to EP300 haploinsufficiency
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen
retinitis pigmentosa
Inheritance: AD Classification: LIMITED Submitted by: G2P

EP300 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 (MetaRNN=0.0051556826).

BP6

Variant 22-41131624-A-G is Benign according to our data. Variant chr22-41131624-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.00077 (1125/1461850) while in subpopulation EAS AF = 0.0172 (681/39700). AF 95% confidence interval is 0.0161. There are 6 homozygotes in GnomAdExome4. There are 542 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 136 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.1519A>G	p.Ser507Gly	missense	Exon 6 of 31	NP_001420.2	Q09472
	EP300	NM_001362843.2		c.1519A>G	p.Ser507Gly	missense	Exon 6 of 30	NP_001349772.1	A0A669KB12

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EP300	ENST00000263253.9	TSL:1 MANE Select	c.1519A>G	p.Ser507Gly	missense	Exon 6 of 31	ENSP00000263253.7	Q09472
EP300	ENST00000916082.1		c.1519A>G	p.Ser507Gly	missense	Exon 6 of 31	ENSP00000586141.1
EP300	ENST00000715703.1		c.1519A>G	p.Ser507Gly	missense	Exon 6 of 31	ENSP00000520505.1	Q09472

Frequencies

GnomAD3 genomes

AF:

0.000894

AC:

136

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.0162

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00191

AC:

479

AN:

250938

AF XY:

0.00173

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00341

Gnomad ASJ exome

AF:

0.00308

Gnomad EAS exome

AF:

0.0164

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000770

AC:

1125

AN:

1461850

Hom.:

Cov.:

AF XY:

0.000745

AC XY:

542

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00394

AC:

176

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00352

AC:

AN:

26136

East Asian (EAS)

AF:

0.0172

AC:

681

AN:

39700

South Asian (SAS)

AF:

0.000325

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53380

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000603

AC:

AN:

1112012

Other (OTH)

AF:

0.00129

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

134

200

267

334

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000893

AC:

136

AN:

152296

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41578

American (AMR)

AF:

0.00216

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3472

East Asian (EAS)

AF:

0.0162

AC:

AN:

5178

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68018

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

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:

0.000996

Hom.:

Bravo

AF:

0.00115

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00173

AC:

210

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Colorectal cancer;C3150941:Rubinstein-Taybi syndrome due to EP300 haploinsufficiency;C4551859:Rubinstein-Taybi syndrome due to CREBBP mutations;C5193035:Menke-Hennekam syndrome 2 (1)

EP300-related disorder (1)

Rubinstein-Taybi syndrome due to EP300 haploinsufficiency (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.37

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.28

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.68

MetaRNN

Benign

0.0052

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.90

PhyloP100

3.1

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.94

REVEL

Benign

0.22

Sift

Benign

0.035

Sift4G

Benign

0.25

Polyphen

0.014

Vest4

0.022

MVP

0.84

ClinPred

0.035

GERP RS

1.0

PromoterAI

-0.031

Neutral

(source)

Varity_R

0.058

gMVP

0.18

Mutation Taster

=77/23

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over