22-41146749-A-G

Position:

chr22-41146749-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001429.4(EP300):c.2064A>G(p.Leu688=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00358 in 1,614,102 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L688L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0028 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0037 ( 13 hom. )

Consequence

EP300
NM_001429.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.97

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 22-41146749-A-G is Benign according to our data. Variant chr22-41146749-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 193844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.97 with no splicing effect.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00367 (5358/1461756) while in subpopulation MID AF= 0.0116 (67/5768). AF 95% confidence interval is 0.00938. There are 13 homozygotes in gnomad4_exome. There are 2746 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High AC in GnomAd4 at 422 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EP300	NM_001429.4 linkuse as main transcript	c.2064A>G	p.Leu688=	synonymous_variant	11/31	ENST00000263253.9
EP300	NM_001362843.2 linkuse as main transcript	c.2054-1088A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EP300	ENST00000263253.9 linkuse as main transcript	c.2064A>G	p.Leu688=	synonymous_variant	11/31	1	NM_001429.4	P2

Frequencies

GnomAD3 genomes

AF:

0.00277

AC:

422

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000844

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00223

Gnomad ASJ

AF:

0.0115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.000754

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00416

Gnomad OTH

AF:

0.00334

GnomAD3 exomes

AF:

0.00307

AC:

772

AN:

251406

Hom.:

AF XY:

0.00310

AC XY:

421

AN XY:

135868

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.00214

Gnomad ASJ exome

AF:

0.00724

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00193

Gnomad FIN exome

AF:

0.000739

Gnomad NFE exome

AF:

0.00452

Gnomad OTH exome

AF:

0.00407

GnomAD4 exome

AF:

0.00367

AC:

5358

AN:

1461756

Hom.:

Cov.:

AF XY:

0.00378

AC XY:

2746

AN XY:

727172

show subpopulations

Gnomad4 AFR exome

AF:

0.000717

Gnomad4 AMR exome

AF:

0.00206

Gnomad4 ASJ exome

AF:

0.00777

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00231

Gnomad4 FIN exome

AF:

0.000711

Gnomad4 NFE exome

AF:

0.00406

Gnomad4 OTH exome

AF:

0.00366

GnomAD4 genome

AF:

0.00277

AC:

422

AN:

152346

Hom.:

Cov.:

AF XY:

0.00248

AC XY:

185

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.000842

Gnomad4 AMR

AF:

0.00222

Gnomad4 ASJ

AF:

0.0115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.000754

Gnomad4 NFE

AF:

0.00416

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00439

Hom.:

Bravo

AF:

0.00300

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00611

EpiControl

AF:

0.00593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 19, 2016	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 14, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	EP300: BP4, BP7, BS1, BS2 -

Rubinstein-Taybi syndrome due to EP300 haploinsufficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

EP300-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 29, 2019

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

0.13

DANN

Benign

0.57

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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