rs2230110

Positions:

• chr22-41141188-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001429.4(EP300):​c.2019T>C​(p.Pro673=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,614,190 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0099 (30 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (20 hom.)
• Consequence: EP300 NM_001429.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.209

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 22-41141188-T-C is Benign according to our data. Variant chr22-41141188-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158558.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-0.209 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00987 (1503/152336) while in subpopulation AFR AF= 0.0342 (1423/41568). AF 95% confidence interval is 0.0328. There are 30 homozygotes in gnomad4. There are 717 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1503 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EP300	NM_001429.4	c.2019T>C	p.Pro673=	synonymous_variant	10/31	ENST00000263253.9
EP300	NM_001362843.2	c.2019T>C	p.Pro673=	synonymous_variant	10/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EP300	ENST00000263253.9	c.2019T>C	p.Pro673=	synonymous_variant	10/31	1	NM_001429.4	P2

Frequencies

GnomAD3 genomes AF: 0.00984 AC: 1498 AN: 152218 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.0342

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00258 AC: 648 AN: 251424 Hom.: 12 AF XY: 0.00180 AC XY: 245 AN XY: 135880

Gnomad AFR exome AF: 0.0349

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00102 AC: 1491 AN: 1461854 Hom.: 20 Cov.: 31 AF XY: 0.000877 AC XY: 638 AN XY: 727224

Gnomad4 AFR exome AF: 0.0353

Gnomad4 AMR exome AF: 0.00219

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000432

Gnomad4 OTH exome AF: 0.00227

GnomAD4 genome AF: 0.00987 AC: 1503 AN: 152336 Hom.: 30 Cov.: 32 AF XY: 0.00962 AC XY: 717 AN XY: 74504

Gnomad4 AFR AF: 0.0342

Gnomad4 AMR AF: 0.00399

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00541 Hom.: 10

Bravo AF: 0.0120

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 04, 2013	- -

EP300-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 15, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 17, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	7.9
DANN	Benign	0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs2230110; hg19: chr22-41537192; COSMIC: COSV54329019;