rs533875300

Positions:

chr22-41178506-TCAG-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PM4_SupportingBP6_Very_StrongBS2

The NM_001429.4(EP300):c.6798_6800delGCA(p.Gln2267del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00378 in 1,613,788 control chromosomes in the GnomAD database, including 15 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0023 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0039 ( 15 hom. )

Consequence

EP300
NM_001429.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:11O:1

Conservation

PhyloP100: 6.12

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:

ENSG00000232754 (HGNC:):

ENSG00000232754 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001429.4. Strenght limited to Supporting due to length of the change: 1aa.

BP6

Variant 22-41178506-TCAG-T is Benign according to our data. Variant chr22-41178506-TCAG-T is described in ClinVar as [Likely_benign]. Clinvar id is 341826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-41178506-TCAG-T is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 343 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EP300	NM_001429.4 linkuse as main transcript	c.6798_6800delGCA	p.Gln2267del	disruptive_inframe_deletion	31/31	ENST00000263253.9	NP_001420.2	Q09472Q7Z6C1
EP300	NM_001362843.2 linkuse as main transcript	c.6720_6722delGCA	p.Gln2241del	disruptive_inframe_deletion	30/30		NP_001349772.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
EP300	ENST00000263253.9 linkuse as main transcript	c.6798_6800delGCA	p.Gln2267del	disruptive_inframe_deletion	31/31	1	NM_001429.4	ENSP00000263253.7	Q09472
EP300	ENST00000674155.1 linkuse as main transcript	c.6720_6722delGCA	p.Gln2241del	disruptive_inframe_deletion	30/30			ENSP00000501078.1	A0A669KB12
ENSG00000232754	ENST00000415054.1 linkuse as main transcript	n.82+4554_82+4556delCTG		intron_variant		3
EP300-AS1	ENST00000420537.1 linkuse as main transcript	n.224-3685_224-3683delCTG		intron_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00226

AC:

343

AN:

151800

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000920

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.0000945

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00392

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00186

AC:

467

AN:

251286

Hom.:

AF XY:

0.00179

AC XY:

243

AN XY:

135814

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.00139

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000457

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00331

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00394

AC:

5753

AN:

1461868

Hom.:

AF XY:

0.00378

AC XY:

2752

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.000538

Gnomad4 AMR exome

AF:

0.00159

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000591

Gnomad4 FIN exome

AF:

0.000169

Gnomad4 NFE exome

AF:

0.00484

Gnomad4 OTH exome

AF:

0.00361

GnomAD4 genome

AF:

0.00226

AC:

343

AN:

151920

Hom.:

Cov.:

AF XY:

0.00199

AC XY:

148

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.000917

Gnomad4 AMR

AF:

0.00216

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.0000945

Gnomad4 NFE

AF:

0.00392

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00268

Hom.:

Bravo

AF:

0.00227

EpiCase

AF:

0.00398

EpiControl

AF:

0.00362

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 24, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	EP300: PM4:Supporting, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 06, 2018	This variant is associated with the following publications: (PMID: 24728327, 27416986, 26960974) -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Rubinstein-Taybi syndrome due to EP300 haploinsufficiency

Pathogenic:1Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Wessex Regional Genetics Laboratory, Salisbury District Hospital	Nov 05, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	May 04, 2023	European Non-Finnish population allele frequency is 0.3034% (rs533875300, 430/128992 alleles, 0 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.4.0, this variant is classified as LIKELY BENIGN. Following criteria are met: BS1 -

Rubinstein-Taybi syndrome due to CREBBP mutations

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not specified

Benign:1Other:1

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 08, 2016	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

EP300-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 15, 2019

This variant is classified as likely 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

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