rs1046088

Positions:

chr22-41178379-A-C

Variant summary

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

The NM_001429.4(EP300):c.6668A>C(p.Gln2223Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0304 in 1,614,146 control chromosomes in the GnomAD database, including 883 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 59 hom., cov: 32)

Exomes 𝑓: 0.031 ( 824 hom. )

Consequence

EP300
NM_001429.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.35

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:

(HGNC:):

links:

EP300-AS1 (HGNC:50504): (EP300 antisense RNA 1)

EP300-AS1 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=0.0054445565).

BP6

Variant 22-41178379-A-C is Benign according to our data. Variant chr22-41178379-A-C is described in ClinVar as [Benign]. Clinvar id is 93744.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0234 (3563/152272) while in subpopulation NFE AF= 0.0357 (2427/68010). AF 95% confidence interval is 0.0345. There are 59 homozygotes in gnomad4. There are 1701 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 3563 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EP300	NM_001429.4 linkuse as main transcript	c.6668A>C	p.Gln2223Pro	missense_variant	31/31	ENST00000263253.9	NP_001420.2
EP300	NM_001362843.2 linkuse as main transcript	c.6590A>C	p.Gln2197Pro	missense_variant	30/30		NP_001349772.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
EP300	ENST00000263253.9 linkuse as main transcript	c.6668A>C	p.Gln2223Pro	missense_variant	31/31	1	NM_001429.4	ENSP00000263253	P2
	ENST00000415054.1 linkuse as main transcript	n.82+4684T>G		intron_variant, non_coding_transcript_variant		3
EP300-AS1	ENST00000420537.1 linkuse as main transcript	n.224-3555T>G		intron_variant, non_coding_transcript_variant		3
EP300	ENST00000674155.1 linkuse as main transcript	c.6590A>C	p.Gln2197Pro	missense_variant	30/30			ENSP00000501078	A2

Frequencies

GnomAD3 genomes

AF:

0.0234

AC:

3563

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00610

Gnomad AMI

AF:

0.0406

Gnomad AMR

AF:

0.0169

Gnomad ASJ

AF:

0.0291

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.0401

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0357

Gnomad OTH

AF:

0.0216

GnomAD3 exomes

AF:

0.0238

AC:

5967

AN:

251224

Hom.:

AF XY:

0.0235

AC XY:

3185

AN XY:

135790

show subpopulations

Gnomad AFR exome

AF:

0.00511

Gnomad AMR exome

AF:

0.0141

Gnomad ASJ exome

AF:

0.0283

Gnomad EAS exome

AF:

0.000326

Gnomad SAS exome

AF:

0.00294

Gnomad FIN exome

AF:

0.0410

Gnomad NFE exome

AF:

0.0348

Gnomad OTH exome

AF:

0.0294

GnomAD4 exome

AF:

0.0311

AC:

45443

AN:

1461874

Hom.:

824

Cov.:

AF XY:

0.0303

AC XY:

22043

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00490

Gnomad4 AMR exome

AF:

0.0145

Gnomad4 ASJ exome

AF:

0.0261

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00326

Gnomad4 FIN exome

AF:

0.0468

Gnomad4 NFE exome

AF:

0.0354

Gnomad4 OTH exome

AF:

0.0290

GnomAD4 genome

AF:

0.0234

AC:

3563

AN:

152272

Hom.:

Cov.:

AF XY:

0.0228

AC XY:

1701

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00609

Gnomad4 AMR

AF:

0.0169

Gnomad4 ASJ

AF:

0.0291

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00269

Gnomad4 FIN

AF:

0.0401

Gnomad4 NFE

AF:

0.0357

Gnomad4 OTH

AF:

0.0218

Alfa

AF:

0.0311

Hom.:

155

Bravo

AF:

0.0214

TwinsUK

AF:

0.0332

AC:

123

ALSPAC

AF:

0.0332

AC:

128

ESP6500AA

AF:

0.00567

AC:

ESP6500EA

AF:

0.0363

AC:

312

ExAC

AF:

0.0241

AC:

2925

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0350

EpiControl

AF:

0.0299

ClinVar

Significance: Benign

Submissions summary: Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2Other:1

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 07, 2013	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Rubinstein-Taybi syndrome due to EP300 haploinsufficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Uncertain

0.59

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.082

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.40

MetaRNN

Benign

0.0054

MetaSVM

Benign

-0.76

MutationAssessor

Benign

2.0

MutationTaster

Benign

0.97

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.18

Sift

Benign

0.17

Sift4G

Benign

0.14

Polyphen

0.0

Vest4

0.11

ClinPred

0.031

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.37

gMVP

0.37

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