rs533875300

chr22-41178506-TCAG-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PM4_Supporting BP6_Very_Strong BS2

The NM_001429.4(EP300):c.6798_6800del(p.Gln2268del) variant causes a 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 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:11 O:1
• Conservation: PhyloP100: 6.12

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]

(HGNC:):

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

ACMG classification

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 GnomAd at 343 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EP300	NM_001429.4	c.6798_6800del	p.Gln2268del	inframe_deletion	31/31	ENST00000263253.9
EP300	NM_001362843.2	c.6720_6722del	p.Gln2242del	inframe_deletion	30/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EP300	ENST00000263253.9	c.6798_6800del	p.Gln2268del	inframe_deletion	31/31	1	NM_001429.4	P2
	ENST00000415054.1	n.82+4554_82+4556del		intron_variant, non_coding_transcript_variant		3
EP300-AS1	ENST00000420537.1	n.224-3685_224-3683del		intron_variant, non_coding_transcript_variant		3
EP300	ENST00000674155.1	c.6720_6722del	p.Gln2242del	inframe_deletion	30/30			A2

Frequencies

GnomAD3 genomes AF: 0.00226 AC: 343 AN: 151800 Hom.: 0 Cov.: 32

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.: 1 AF XY: 0.00179 AC XY: 243 AN XY: 135814

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.: 15 AF XY: 0.00378 AC XY: 2752 AN XY: 727232

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.: 0 Cov.: 32 AF XY: 0.00199 AC XY: 148 AN XY: 74268

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.: 0

Bravo AF: 0.00227

EpiCase AF: 0.00398

EpiControl AF: 0.00362

ClinVar

Significance: Benign/Likely benign

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

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

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	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 24, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	EP300: PM4:Supporting, BS1 -

Rubinstein-Taybi syndrome due to EP300 haploinsufficiency Pathogenic:1 Benign:2

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 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Wessex Regional Genetics Laboratory, Salisbury District Hospital	Nov 05, 2019	- -

Rubinstein-Taybi syndrome due to CREBBP mutations Benign:2

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

not specified Benign:1 Other: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, criteria provided, single submitter

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

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

Other links and lift over

dbSNP: rs533875300; hg19: chr22-41574510;