22-41146776-T-G

Position:

chr22-41146776-T-G

Variant summary

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

The NM_001429.4(EP300):c.2091T>G(p.Ser697Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00528 in 1,614,124 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0036 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0055 ( 41 hom. )

Consequence

EP300
NM_001429.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: 4.13

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 (HGNC:):

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=0.009304136).

BP6

Variant 22-41146776-T-G is Benign according to our data. Variant chr22-41146776-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 134035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-41146776-T-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00545 (7967/1461790) while in subpopulation NFE AF= 0.00673 (7484/1111922). AF 95% confidence interval is 0.0066. There are 41 homozygotes in gnomad4_exome. There are 3825 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High AC in GnomAd4 at 549 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EP300	NM_001429.4 linkuse as main transcript	c.2091T>G	p.Ser697Arg	missense_variant	11/31	ENST00000263253.9	NP_001420.2	Q09472Q7Z6C1
EP300	NM_001362843.2 linkuse as main transcript	c.2054-1061T>G		intron_variant			NP_001349772.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EP300	ENST00000263253.9 linkuse as main transcript	c.2091T>G	p.Ser697Arg	missense_variant	11/31	1	NM_001429.4	ENSP00000263253.7		Q09472

Frequencies

GnomAD3 genomes

AF:

0.00361

AC:

549

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00142

Gnomad AMI

AF:

0.0351

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00610

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00348

AC:

876

AN:

251476

Hom.:

AF XY:

0.00336

AC XY:

457

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.00135

Gnomad AMR exome

AF:

0.00121

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000686

Gnomad FIN exome

AF:

0.00125

Gnomad NFE exome

AF:

0.00648

Gnomad OTH exome

AF:

0.00358

GnomAD4 exome

AF:

0.00545

AC:

7967

AN:

1461790

Hom.:

Cov.:

AF XY:

0.00526

AC XY:

3825

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.00111

Gnomad4 AMR exome

AF:

0.00132

Gnomad4 ASJ exome

AF:

0.000574

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000661

Gnomad4 FIN exome

AF:

0.00157

Gnomad4 NFE exome

AF:

0.00673

Gnomad4 OTH exome

AF:

0.00379

GnomAD4 genome

AF:

0.00360

AC:

549

AN:

152334

Hom.:

Cov.:

AF XY:

0.00354

AC XY:

264

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.00142

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00141

Gnomad4 NFE

AF:

0.00610

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00502

Hom.:

Bravo

AF:

0.00377

TwinsUK

AF:

0.00890

AC:

ALSPAC

AF:

0.00623

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00465

AC:

ExAC

AF:

0.00388

AC:

471

EpiCase

AF:

0.00540

EpiControl

AF:

0.00557

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	EP300: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2Other:1

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 27, 2021	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 27, 2014	- -

Rubinstein-Taybi syndrome due to EP300 haploinsufficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Rubinstein-Taybi syndrome due to CREBBP mutations

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Intellectual disability

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.045

MetaRNN

Benign

0.0093

MetaSVM

Uncertain

-0.22

MutationAssessor

Benign

0.69

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.3

REVEL

Uncertain

0.31

Sift

Uncertain

0.0070

Sift4G

Benign

0.58

Polyphen

0.96

Vest4

0.58

MutPred

0.25

Gain of catalytic residue at S697 (P = 0.017);

MVP

0.79

ClinPred

0.020

GERP RS

5.8

Varity_R

0.19

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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