22-41093056-C-A

Variant names:

• chr22-41093056-C-A
• rs777392825
• NM_001429.4:c.52C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001429.4(EP300):​c.52C>A​(p.Leu18Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L18V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EP300 NM_001429.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.81
• 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 Gene-Disease associations (from GenCC):

• Rubinstein-Taybi syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: Illumina
• Rubinstein-Taybi syndrome due to EP300 haploinsufficiency

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• retinitis pigmentosa

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ENSG00000296654 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37570643).

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.52C>A	p.Leu18Ile	missense	Exon 1 of 31	NP_001420.2	Q09472
	EP300	NM_001362843.2		c.52C>A	p.Leu18Ile	missense	Exon 1 of 30	NP_001349772.1	A0A669KB12

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EP300	ENST00000263253.9	TSL:1 MANE Select	c.52C>A	p.Leu18Ile	missense	Exon 1 of 31	ENSP00000263253.7	Q09472
	EP300	ENST00000916082.1		c.52C>A	p.Leu18Ile	missense	Exon 1 of 31	ENSP00000586141.1
	EP300	ENST00000715703.1		c.52C>A	p.Leu18Ile	missense	Exon 1 of 31	ENSP00000520505.1	Q09472

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	0.57	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		6.8
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.39
Sift	Benign	0.077	T
Sift4G	Benign	0.14	T
Polyphen		0.99	D
Vest4		0.39
MutPred		0.17		Loss of loop (P = 0.0603)
MVP		0.80
ClinPred		0.97	D
GERP RS		4.7
PromoterAI		-0.026	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.35
gMVP		0.14
Mutation Taster		=62/38	polymorphism

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: rs777392825; hg19: chr22-41489060; COSMIC: COSV104550787; COSMIC: COSV104550787;