22-41152004-A-G

Position:

chr22-41152004-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001429.4(EP300):c.2989A>G(p.Ile997Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.283 in 1,613,848 control chromosomes in the GnomAD database, including 71,539 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 5329 hom., cov: 31)

Exomes 𝑓: 0.29 ( 66210 hom. )

Consequence

EP300
NM_001429.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.95

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=1.5753508E-4).

BP6

Variant 22-41152004-A-G is Benign according to our data. Variant chr22-41152004-A-G is described in ClinVar as [Benign]. Clinvar id is 93736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-41152004-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.412 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EP300	NM_001429.4 linkuse as main transcript	c.2989A>G	p.Ile997Val	missense_variant	15/31	ENST00000263253.9
EP300	NM_001362843.2 linkuse as main transcript	c.2911A>G	p.Ile971Val	missense_variant	14/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
EP300	ENST00000263253.9 linkuse as main transcript	c.2989A>G	p.Ile997Val	missense_variant	15/31	1	NM_001429.4	P2
EP300	ENST00000674155.1 linkuse as main transcript	c.2911A>G	p.Ile971Val	missense_variant	14/30			A2
EP300	ENST00000703544.1 linkuse as main transcript	c.*909A>G		3_prime_UTR_variant, NMD_transcript_variant	14/30
EP300	ENST00000703545.1 linkuse as main transcript	c.*1359A>G		3_prime_UTR_variant, NMD_transcript_variant	13/17

Frequencies

GnomAD3 genomes

AF:

0.231

AC:

35091

AN:

152024

Hom.:

5319

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0585

Gnomad AMI

AF:

0.427

Gnomad AMR

AF:

0.420

Gnomad ASJ

AF:

0.321

Gnomad EAS

AF:

0.0583

Gnomad SAS

AF:

0.373

Gnomad FIN

AF:

0.318

Gnomad MID

AF:

0.239

Gnomad NFE

AF:

0.275

Gnomad OTH

AF:

0.259

GnomAD3 exomes

AF:

0.310

AC:

77896

AN:

251398

Hom.:

15059

AF XY:

0.309

AC XY:

41940

AN XY:

135868

show subpopulations

Gnomad AFR exome

AF:

0.0532

Gnomad AMR exome

AF:

0.599

Gnomad ASJ exome

AF:

0.327

Gnomad EAS exome

AF:

0.0626

Gnomad SAS exome

AF:

0.371

Gnomad FIN exome

AF:

0.314

Gnomad NFE exome

AF:

0.279

Gnomad OTH exome

AF:

0.328

GnomAD4 exome

AF:

0.289

AC:

421891

AN:

1461706

Hom.:

66210

Cov.:

AF XY:

0.291

AC XY:

211498

AN XY:

727158

show subpopulations

Gnomad4 AFR exome

AF:

0.0483

Gnomad4 AMR exome

AF:

0.576

Gnomad4 ASJ exome

AF:

0.327

Gnomad4 EAS exome

AF:

0.0414

Gnomad4 SAS exome

AF:

0.374

Gnomad4 FIN exome

AF:

0.318

Gnomad4 NFE exome

AF:

0.285

Gnomad4 OTH exome

AF:

0.281

GnomAD4 genome

AF:

0.231

AC:

35108

AN:

152142

Hom.:

5329

Cov.:

AF XY:

0.240

AC XY:

17831

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.0583

Gnomad4 AMR

AF:

0.421

Gnomad4 ASJ

AF:

0.321

Gnomad4 EAS

AF:

0.0582

Gnomad4 SAS

AF:

0.374

Gnomad4 FIN

AF:

0.318

Gnomad4 NFE

AF:

0.275

Gnomad4 OTH

AF:

0.256

Alfa

AF:

0.269

Hom.:

12668

Bravo

AF:

0.234

TwinsUK

AF:

0.298

AC:

1106

ALSPAC

AF:

0.275

AC:

1059

ESP6500AA

AF:

0.0604

AC:

266

ESP6500EA

AF:

0.280

AC:

2411

ExAC

AF:

0.296

AC:

35902

Asia WGS

AF:

0.176

AC:

613

AN:

3478

EpiCase

AF:

0.287

EpiControl

AF:

0.277

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 10, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Rubinstein-Taybi syndrome due to EP300 haploinsufficiency

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

Menke-Hennekam syndrome 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 17, 2018

This variant is associated with the following publications: (PMID: 22231458) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.50

CADD

Benign

9.4

DANN

Benign

0.77

DEOGEN2

Benign

0.34

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.63

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.59

MetaRNN

Benign

0.00016

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.0

MutationTaster

Benign

1.0

PrimateAI

Benign

0.30

PROVEAN

Benign

0.35

REVEL

Benign

0.24

Sift

Benign

0.31

Sift4G

Benign

0.39

Polyphen

0.0

Vest4

0.014

ClinPred

0.0097

GERP RS

3.6

Varity_R

0.029

gMVP

0.061

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