rs1555911573

Variant names:

• chr22-41172551-C-T
• rs1555911573
• NM_001429.4:c.4505C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001429.4(EP300):​c.4505C>T​(p.Pro1502Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EP300 NM_001429.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 7.82
• Publications: 1 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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985

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.4505C>T	p.Pro1502Leu	missense	Exon 28 of 31	NP_001420.2
	EP300	NM_001362843.2		c.4427C>T	p.Pro1476Leu	missense	Exon 27 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.4505C>T	p.Pro1502Leu	missense	Exon 28 of 31	ENSP00000263253.7
	EP300	ENST00000715703.1		c.4505C>T	p.Pro1502Leu	missense	Exon 28 of 31	ENSP00000520505.1
	EP300	ENST00000674155.1		c.4427C>T	p.Pro1476Leu	missense	Exon 27 of 30	ENSP00000501078.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Mar 23, 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

May 17, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with EP300-related disease. ClinVar contains an entry for this variant (Variation ID: 438291). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with leucine at codon 1502 of the EP300 protein (p.Pro1502Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.8
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-9.7	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.026	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.92		Loss of methylation at K1499 (P = 0.0489)
MVP		0.95
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.73
gMVP		0.90
Mutation Taster		=4/96	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1555911573; hg19: chr22-41568555; COSMIC: COSV54326740; COSMIC: COSV54326740;