rs181755354

Variant names:

• chr22-41127755-G-C
• rs181755354
• NM_001429.4:c.1168+7G>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001429.4(EP300):​c.1168+7G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00941 in 1,614,094 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0070 (7 hom., cov: 31)
  • Exomes 𝑓: 0.0097 (87 hom.)
• Consequence: EP300 NM_001429.4 splice_region, intron
• Scores: Splicing: ADA: 0.00003331
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.513
• 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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 22-41127755-G-C is Benign according to our data. Variant chr22-41127755-G-C is described in ClinVar as Benign. ClinVar VariationId is 210937.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 1068 AD gene.

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.1168+7G>C		splice_region intron	N/A	NP_001420.2	Q09472
	EP300	NM_001362843.2		c.1168+7G>C		splice_region intron	N/A	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.1168+7G>C		splice_region intron	N/A	ENSP00000263253.7	Q09472
	EP300	ENST00000916082.1		c.1168+7G>C		splice_region intron	N/A	ENSP00000586141.1
	EP300	ENST00000715703.1		c.1168+7G>C		splice_region intron	N/A	ENSP00000520505.1	Q09472

Frequencies

GnomAD3 genomes AF: 0.00702 AC: 1068 AN: 152238 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.00210

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00307

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00461

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0127

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00688 AC: 1721 AN: 250008 AF XY: 0.00707

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.00405

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00513

Gnomad NFE exome AF: 0.0120

Gnomad OTH exome AF: 0.00947

GnomAD4 exome AF: 0.00966 AC: 14117 AN: 1461738 Hom.: 87 Cov.: 31 AF XY: 0.00959 AC XY: 6977 AN XY: 727162

African (AFR) AF: 0.00167 AC: 56 AN: 33478

American (AMR) AF: 0.00405 AC: 181 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00291 AC: 76 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000186 AC: 16 AN: 86226

European-Finnish (FIN) AF: 0.00635 AC: 339 AN: 53390

Middle Eastern (MID) AF: 0.00263 AC: 15 AN: 5702

European-Non Finnish (NFE) AF: 0.0116 AC: 12860 AN: 1111998

Other (OTH) AF: 0.00951 AC: 574 AN: 60386

GnomAD4 genome AF: 0.00701 AC: 1068 AN: 152356 Hom.: 7 Cov.: 31 AF XY: 0.00652 AC XY: 486 AN XY: 74496

African (AFR) AF: 0.00209 AC: 87 AN: 41582

American (AMR) AF: 0.00307 AC: 47 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00461 AC: 49 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0127 AC: 867 AN: 68040

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.0121 Hom.: 2

Bravo AF: 0.00669

EpiCase AF: 0.0110

EpiControl AF: 0.0109

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Rubinstein-Taybi syndrome due to EP300 haploinsufficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.8
DANN	Benign	0.50
PhyloP100		0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000033
dbscSNV1_RF	Benign	0.0020
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: rs181755354; hg19: chr22-41523759; COSMIC: COSV54342657;