rs1555910602

Positions:

• chr22-41164054-TTTG-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4_Supporting PP5

The NM_001429.4(EP300):​c.3734_3736delTTG​(p.Val1245del) variant causes a disruptive inframe deletion 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 disruptive_inframe_deletion
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 10.0

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001429.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 22-41164054-TTTG-T is Pathogenic according to our data. Variant chr22-41164054-TTTG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 438292.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.3734_3736delTTG	p.Val1245del	disruptive_inframe_deletion	22/31	ENST00000263253.9	NP_001420.2
EP300	NM_001362843.2	c.3656_3658delTTG	p.Val1219del	disruptive_inframe_deletion	21/30		NP_001349772.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EP300	ENST00000263253.9	c.3734_3736delTTG	p.Val1245del	disruptive_inframe_deletion	22/31	1	NM_001429.4	ENSP00000263253.7

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

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Rubinstein-Taybi syndrome due to EP300 haploinsufficiency Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Feb 12, 2016

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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: rs1555910602; hg19: chr22-41560058;