rs142030651

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001429.4(EP300):c.631G>A(p.Gly211Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0082 in 1,614,214 control chromosomes in the GnomAD database, including 76 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G211D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0064 ( 6 hom., cov: 33)

Exomes 𝑓: 0.0084 ( 70 hom. )

Consequence

EP300
NM_001429.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 3.32

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009073317).

BP6

Variant 22-41117723-G-A is Benign according to our data. Variant chr22-41117723-G-A is described in ClinVar as [Benign]. Clinvar id is 134043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-41117723-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00635 (968/152336) while in subpopulation AMR AF= 0.0142 (217/15290). AF 95% confidence interval is 0.0126. There are 6 homozygotes in gnomad4. There are 453 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd at 969 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EP300	NM_001429.4 linkuse as main transcript	c.631G>A	p.Gly211Ser	missense_variant	2/31	ENST00000263253.9
EP300	NM_001362843.2 linkuse as main transcript	c.631G>A	p.Gly211Ser	missense_variant	2/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EP300	ENST00000263253.9 linkuse as main transcript	c.631G>A	p.Gly211Ser	missense_variant	2/31	1	NM_001429.4	P2

Frequencies

GnomAD3 genomes

AF:

0.00637

AC:

969

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00193

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.0143

Gnomad ASJ

AF:

0.0107

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00879

Gnomad OTH

AF:

0.00908

GnomAD3 exomes

AF:

0.00606

AC:

1524

AN:

251410

Hom.:

AF XY:

0.00592

AC XY:

804

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.00166

Gnomad AMR exome

AF:

0.00946

Gnomad ASJ exome

AF:

0.0113

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00129

Gnomad NFE exome

AF:

0.00838

Gnomad OTH exome

AF:

0.0119

GnomAD4 exome

AF:

0.00840

AC:

12274

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00826

AC XY:

6004

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00137

Gnomad4 AMR exome

AF:

0.0102

Gnomad4 ASJ exome

AF:

0.0118

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.00139

Gnomad4 NFE exome

AF:

0.00978

Gnomad4 OTH exome

AF:

0.00818

GnomAD4 genome

AF:

0.00635

AC:

968

AN:

152336

Hom.:

Cov.:

AF XY:

0.00608

AC XY:

453

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00192

Gnomad4 AMR

AF:

0.0142

Gnomad4 ASJ

AF:

0.0107

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000753

Gnomad4 NFE

AF:

0.00879

Gnomad4 OTH

AF:

0.00899

Alfa

AF:

0.00759

Hom.:

Bravo

AF:

0.00694

TwinsUK

AF:

0.00971

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00779

AC:

ExAC

AF:

0.00535

AC:

650

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00829

EpiControl

AF:

0.00966

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	EP300: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 20, 2018	- -

EP300-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 19, 2022

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Rubinstein-Taybi syndrome due to EP300 haploinsufficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.15

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.59

Eigen

Benign

0.013

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.74

MetaRNN

Benign

0.0091

MetaSVM

Benign

-0.52

MutationAssessor

Benign

1.5

MutationTaster

Benign

0.97

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.35

Sift

Benign

0.051

Sift4G

Benign

0.095

Polyphen

0.14

Vest4

0.34

MVP

0.87

ClinPred

0.014

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.081

gMVP

0.45

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over