rs587778256

chr22-41178336-AACCAGTTCCAGC-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 3P and 12B. PM4 PP3 BP6_Very_Strong BS2

The NM_001429.4(EP300):c.6627_6638del(p.Asn2209_Gln2213delinsLys) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00186 in 1,614,128 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (5 hom.)
• Consequence: EP300 NM_001429.4 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 U:1 B:10 O:1
• Conservation: PhyloP100: 7.86

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 -9 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001429.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• BP6: Variant 22-41178336-AACCAGTTCCAGC-A is Benign according to our data. Variant chr22-41178336-AACCAGTTCCAGC-A is described in ClinVar as [Likely_benign]. Clinvar id is 253313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-41178336-AACCAGTTCCAGC-A is described in Lovd as [Likely_pathogenic]. Variant chr22-41178336-AACCAGTTCCAGC-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 252 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EP300	NM_001429.4	c.6627_6638del	p.Asn2209_Gln2213delinsLys	inframe_deletion	31/31	ENST00000263253.9
EP300	NM_001362843.2	c.6549_6560del	p.Asn2183_Gln2187delinsLys	inframe_deletion	30/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EP300	ENST00000263253.9	c.6627_6638del	p.Asn2209_Gln2213delinsLys	inframe_deletion	31/31	1	NM_001429.4	P2
	ENST00000415054.1	n.82+4715_82+4726del		intron_variant, non_coding_transcript_variant		3
EP300-AS1	ENST00000420537.1	n.224-3524_224-3513del		intron_variant, non_coding_transcript_variant		3
EP300	ENST00000674155.1	c.6549_6560del	p.Asn2183_Gln2187delinsLys	inframe_deletion	30/30			A2

Frequencies

GnomAD3 genomes AF: 0.00166 AC: 252 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00309

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00155 AC: 390 AN: 251338 Hom.: 0 AF XY: 0.00149 AC XY: 203 AN XY: 135864

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00213

Gnomad NFE exome AF: 0.00261

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00188 AC: 2748 AN: 1461886 Hom.: 5 AF XY: 0.00189 AC XY: 1371 AN XY: 727244

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000626

Gnomad4 ASJ exome AF: 0.000497

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00247

Gnomad4 NFE exome AF: 0.00219

Gnomad4 OTH exome AF: 0.00204

GnomAD4 genome AF: 0.00166 AC: 252 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.00138 AC XY: 103 AN XY: 74442

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00309

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00327 Hom.: 0

Bravo AF: 0.00120

EpiCase AF: 0.00262

EpiControl AF: 0.00196

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Uncertain:1 Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

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	Oct 01, 2023	EP300: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2019	This variant is associated with the following publications: (PMID: 29506490, 33337535) -
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)	-	- -

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

Pathogenic, flagged submission	research	Fundacion Rioja Salud, Center for Biomedical Research (CIBIR)	Jul 01, 2016	- -
Uncertain significance, flagged submission	clinical testing	Dr. med. U. Finckh, Human Genetics, Eurofins MVZ	Oct 20, 2022	This EP300 variant deletes 12 nucleotides leading to an inframe deletion of codons 2209-2213 and insertion of 1 Lysine. It has been described occurring de novo in patients with Rubinstein-Taybi syndrome (PMID: 29506490, 33337535) but also is present in approx. 0.6% of the european general population. Either the variant was found randomly and without causal relationship in affected patients or it predisposes - seeming less likely - to a low-penetrance / variable-expression form of the disease, possibly influenced by additional factors. Internal data: Heterozygous in a proband with early childhood autism spectrum disorder not displaying any other obvious similarities to Rubinstein-Taybi syndrome. Subsequently, the variant was also detected in the unaffected father. We classify the variant as uncertain. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 23, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 23, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

See cases Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Jan 14, 2022

ACMG classification criteria: BS1, BS2 -

EP300-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 26, 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). -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587778256; hg19: chr22-41574340;