22-41093047-C-CG

Position:

• chr22-41093047-C-CG

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001429.4(EP300):​c.45dupG​(p.Pro16fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EP300 NM_001429.4 frameshift
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.66

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 25 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-41093047-C-CG is Pathogenic according to our data. Variant chr22-41093047-C-CG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3349960.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EP300	NM_001429.4	c.45dupG	p.Pro16fs	frameshift_variant	1/31	ENST00000263253.9	NP_001420.2
EP300	NM_001362843.2	c.45dupG	p.Pro16fs	frameshift_variant	1/30		NP_001349772.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EP300	ENST00000263253.9	c.45dupG	p.Pro16fs	frameshift_variant	1/31	1	NM_001429.4	ENSP00000263253.7
EP300	ENST00000674155.1	c.45dupG	p.Pro16fs	frameshift_variant	1/30			ENSP00000501078.1
EP300	ENST00000703544.1	n.45dupG		non_coding_transcript_exon_variant	1/30			ENSP00000515365.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

EP300-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 27, 2024

The EP300 c.45dupG variant is predicted to result in a frameshift and premature protein termination (p.Pro16Alafs*2). To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. Frameshift variants in EP300 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-41489051;