rs797045560

Variant names:

• chr22-41178622-CCAAT-C
• rs797045560
• NM_001429.4:c.6915_6918delTCAA

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_001429.4(EP300):​c.6915_6918delTCAA​(p.Asn2305LysfsTer47) 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EP300 NM_001429.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.30
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 11 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-41178622-CCAAT-C is Pathogenic according to our data. Variant chr22-41178622-CCAAT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 210941.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001429.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EP300	NM_001429.4	MANE Select	c.6915_6918delTCAA	p.Asn2305LysfsTer47	frameshift	Exon 31 of 31	NP_001420.2
	EP300	NM_001362843.2		c.6837_6840delTCAA	p.Asn2279LysfsTer47	frameshift	Exon 30 of 30	NP_001349772.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EP300	ENST00000263253.9	TSL:1 MANE Select	c.6915_6918delTCAA	p.Asn2305LysfsTer47	frameshift	Exon 31 of 31	ENSP00000263253.7
	EP300	ENST00000916082.1		c.6945_6948delTCAA	p.Asn2315LysfsTer47	frameshift	Exon 31 of 31	ENSP00000586141.1
	EP300	ENST00000715703.1		c.6915_6918delTCAA	p.Asn2305LysfsTer47	frameshift	Exon 31 of 31	ENSP00000520505.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Rubinstein-Taybi syndrome due to EP300 haploinsufficiency (1)
1	-	-	Rubinstein-Taybi syndrome due to EP300 haploinsufficiency;C5193035:Menke-Hennekam syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3
Mutation Taster		=10/190	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs797045560; hg19: chr22-41574626; COSMIC: COSV54339811; COSMIC: COSV54339811;