rs17002316

chr22-41149746-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001429.4(EP300):c.2380-15T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 1,613,804 control chromosomes in the GnomAD database, including 1,437 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (433 hom., cov: 31)
  • Exomes 𝑓: 0.0092 (1004 hom.)
• Consequence: EP300 NM_001429.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.152

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 22-41149746-T-C is Benign according to our data. Variant chr22-41149746-T-C is described in ClinVar as [Benign]. Clinvar id is 158559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.196 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EP300	NM_001429.4	c.2380-15T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000263253.9
EP300	NM_001362843.2	c.2302-15T>C		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EP300	ENST00000263253.9	c.2380-15T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001429.4	P2

Frequencies

GnomAD3 genomes AF: 0.0415 AC: 6310 AN: 152104 Hom.: 432 Cov.: 31

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0145

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.207

Gnomad SAS AF: 0.0143

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.0336

GnomAD3 exomes AF: 0.0264 AC: 6633 AN: 250922 Hom.: 601 AF XY: 0.0227 AC XY: 3085 AN XY: 135714

Gnomad AFR exome AF: 0.116

Gnomad AMR exome AF: 0.00625

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.230

Gnomad SAS exome AF: 0.00654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000458

Gnomad OTH exome AF: 0.0119

GnomAD4 exome AF: 0.00923 AC: 13492 AN: 1461582 Hom.: 1004 Cov.: 32 AF XY: 0.00885 AC XY: 6436 AN XY: 727116

Gnomad4 AFR exome AF: 0.117

Gnomad4 AMR exome AF: 0.00760

Gnomad4 ASJ exome AF: 0.000497

Gnomad4 EAS exome AF: 0.177

Gnomad4 SAS exome AF: 0.00757

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000329

Gnomad4 OTH exome AF: 0.0189

GnomAD4 genome AF: 0.0415 AC: 6317 AN: 152222 Hom.: 433 Cov.: 31 AF XY: 0.0411 AC XY: 3063 AN XY: 74436

Gnomad4 AFR AF: 0.116

Gnomad4 AMR AF: 0.0145

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.206

Gnomad4 SAS AF: 0.0141

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000838

Gnomad4 OTH AF: 0.0332

Alfa AF: 0.0182 Hom.: 20

Bravo AF: 0.0457

Asia WGS AF: 0.0810 AC: 282 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

Rubinstein-Taybi syndrome due to EP300 haploinsufficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 27, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	6.2
Dann	Benign	0.62

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: rs17002316; hg19: chr22-41545750; COSMIC: COSV54333432; COSMIC: COSV54333432;