rs2294976

Positions:

• chr22-41168704-C-A
• chr22-41168704-C-G
• chr22-41168704-C-T

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.4026-17C>A 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 0.0882 in 1,614,098 control chromosomes in the GnomAD database, including 7,057 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.074 (556 hom., cov: 32)
  • Exomes 𝑓: 0.090 (6501 hom.)
• Consequence: EP300 NM_001429.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.00700

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=-0.79).
• BP6: Variant 22-41168704-C-A is Benign according to our data. Variant chr22-41168704-C-A is described in ClinVar as [Benign]. Clinvar id is 93740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-41168704-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EP300	NM_001429.4	c.4026-17C>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000263253.9
EP300	NM_001362843.2	c.3948-17C>A		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EP300	ENST00000263253.9	c.4026-17C>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001429.4	P2
EP300	ENST00000674155.1	c.3948-17C>A		splice_polypyrimidine_tract_variant, intron_variant				A2
EP300	ENST00000703544.1	c.*1946-17C>A		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant
EP300	ENST00000635584.1	n.351-17C>A		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0735 AC: 11182 AN: 152158 Hom.: 547 Cov.: 32

Gnomad AFR AF: 0.0280

Gnomad AMI AF: 0.0330

Gnomad AMR AF: 0.0585

Gnomad ASJ AF: 0.0717

Gnomad EAS AF: 0.168

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.0879

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.0925

Gnomad OTH AF: 0.0866

GnomAD3 exomes AF: 0.0888 AC: 22314 AN: 251400 Hom.: 1222 AF XY: 0.0921 AC XY: 12521 AN XY: 135892

Gnomad AFR exome AF: 0.0253

Gnomad AMR exome AF: 0.0466

Gnomad ASJ exome AF: 0.0771

Gnomad EAS exome AF: 0.169

Gnomad SAS exome AF: 0.114

Gnomad FIN exome AF: 0.0880

Gnomad NFE exome AF: 0.0919

Gnomad OTH exome AF: 0.0913

GnomAD4 exome AF: 0.0897 AC: 131155 AN: 1461822 Hom.: 6501 Cov.: 33 AF XY: 0.0909 AC XY: 66122 AN XY: 727210

Gnomad4 AFR exome AF: 0.0260

Gnomad4 AMR exome AF: 0.0496

Gnomad4 ASJ exome AF: 0.0794

Gnomad4 EAS exome AF: 0.175

Gnomad4 SAS exome AF: 0.110

Gnomad4 FIN exome AF: 0.0886

Gnomad4 NFE exome AF: 0.0885

Gnomad4 OTH exome AF: 0.0939

GnomAD4 genome AF: 0.0736 AC: 11204 AN: 152276 Hom.: 556 Cov.: 32 AF XY: 0.0728 AC XY: 5419 AN XY: 74456

Gnomad4 AFR AF: 0.0280

Gnomad4 AMR AF: 0.0585

Gnomad4 ASJ AF: 0.0717

Gnomad4 EAS AF: 0.169

Gnomad4 SAS AF: 0.108

Gnomad4 FIN AF: 0.0879

Gnomad4 NFE AF: 0.0925

Gnomad4 OTH AF: 0.0961

Alfa AF: 0.0881 Hom.: 907

Bravo AF: 0.0690

Asia WGS AF: 0.182 AC: 629 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	Eurofins Ntd Llc (ga)	Apr 03, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Aug 11, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.9
DANN	Benign	0.33
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs2294976; hg19: chr22-41564708; COSMIC: COSV54326727; COSMIC: COSV54326727;