rs533875300

Variant names:

• chr22-41178506-TCAG-T
• rs533875300
• NM_001429.4:c.6798_6800delGCA

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PM4_Supporting BP6_Very_Strong BS2

The NM_001429.4(EP300):​c.6798_6800delGCA​(p.Gln2267del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00378 in 1,613,788 control chromosomes in the GnomAD database, including 15 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (15 hom.)
• Consequence: EP300 NM_001429.4 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:11 O:1
• Conservation: PhyloP100: 6.12
• Publications: 5 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-AS1 (HGNC:50504): (EP300 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001429.4. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 22-41178506-TCAG-T is Benign according to our data. Variant chr22-41178506-TCAG-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 341826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 343 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.6798_6800delGCA	p.Gln2267del	disruptive_inframe_deletion	Exon 31 of 31	NP_001420.2	Q09472
	EP300	NM_001362843.2		c.6720_6722delGCA	p.Gln2241del	disruptive_inframe_deletion	Exon 30 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.6798_6800delGCA	p.Gln2267del	disruptive_inframe_deletion	Exon 31 of 31	ENSP00000263253.7	Q09472
	EP300	ENST00000916082.1		c.6828_6830delGCA	p.Gln2277del	disruptive_inframe_deletion	Exon 31 of 31	ENSP00000586141.1
	EP300	ENST00000715703.1		c.6798_6800delGCA	p.Gln2267del	disruptive_inframe_deletion	Exon 31 of 31	ENSP00000520505.1	Q09472

Frequencies

GnomAD3 genomes AF: 0.00226 AC: 343 AN: 151800 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000920

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00392

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00186 AC: 467 AN: 251286 AF XY: 0.00179

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00331

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00394 AC: 5753 AN: 1461868 Hom.: 15 AF XY: 0.00378 AC XY: 2752 AN XY: 727232

African (AFR) AF: 0.000538 AC: 18 AN: 33480

American (AMR) AF: 0.00159 AC: 71 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000591 AC: 51 AN: 86258

European-Finnish (FIN) AF: 0.000169 AC: 9 AN: 53402

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00484 AC: 5380 AN: 1112004

Other (OTH) AF: 0.00361 AC: 218 AN: 60396

GnomAD4 genome AF: 0.00226 AC: 343 AN: 151920 Hom.: 0 Cov.: 32 AF XY: 0.00199 AC XY: 148 AN XY: 74268

African (AFR) AF: 0.000917 AC: 38 AN: 41432

American (AMR) AF: 0.00216 AC: 33 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4808

European-Finnish (FIN) AF: 0.0000945 AC: 1 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00392 AC: 266 AN: 67922

Other (OTH) AF: 0.00190 AC: 4 AN: 2106

Alfa AF: 0.00268 Hom.: 0

Bravo AF: 0.00227

EpiCase AF: 0.00398

EpiControl AF: 0.00362

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
1	-	2	Rubinstein-Taybi syndrome due to EP300 haploinsufficiency (3)
-	-	2	Rubinstein-Taybi syndrome due to CREBBP mutations (2)
-	-	1	EP300-related disorder (1)
-	-	1	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.1
Mutation Taster		=78/22	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: rs533875300; hg19: chr22-41574510; COSMIC: COSV54325791; COSMIC: COSV54325791;