22-41170489-TACCCAA-T

Variant names:

• chr22-41170489-TACCCAA-T
• rs1555911316
• NM_001429.4:c.4371_4376delACCCAA

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM4 PP3 PP5_Moderate

The NM_001429.4(EP300):​c.4371_4376delACCCAA​(p.Ile1457_Lys1459delinsMet) 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EP300 NM_001429.4 disruptive_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.22
• 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 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001429.4
• PM2: Very rare variant in population databases, with high coverage
• 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
• PP5: Variant 22-41170489-TACCCAA-T is Pathogenic according to our data. Variant chr22-41170489-TACCCAA-T is described in ClinVar as Pathogenic. ClinVar VariationId is 438290.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EP300	NM_001429.4	MANE Select	c.4371_4376delACCCAA	p.Ile1457_Lys1459delinsMet	disruptive_inframe_deletion	Exon 27 of 31	NP_001420.2
	EP300	NM_001362843.2		c.4293_4298delACCCAA	p.Ile1431_Lys1433delinsMet	disruptive_inframe_deletion	Exon 26 of 30	NP_001349772.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EP300	ENST00000263253.9	TSL:1 MANE Select	c.4371_4376delACCCAA	p.Ile1457_Lys1459delinsMet	disruptive_inframe_deletion	Exon 27 of 31	ENSP00000263253.7
	EP300	ENST00000715703.1		c.4371_4376delACCCAA	p.Ile1457_Lys1459delinsMet	disruptive_inframe_deletion	Exon 27 of 31	ENSP00000520505.1
	EP300	ENST00000674155.1		c.4293_4298delACCCAA	p.Ile1431_Lys1433delinsMet	disruptive_inframe_deletion	Exon 26 of 30	ENSP00000501078.1

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

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Rubinstein-Taybi syndrome due to EP300 haploinsufficiency Pathogenic:1

Sep 15, 2016

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

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Pathogenic:1

May 17, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in a patient in published literature with features of Rubinstein-Taybi syndrome (Fergelot et al., 2016); In-frame deletion of 3 amino acids and insertion of 1 incorrect amino acid in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27648933)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.2
Mutation Taster		=10/190	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1555911316; hg19: chr22-41566493;