22-41177259-CCCACTCCTG-C

Position:

• chr22-41177259-CCCACTCCTG-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM4 PP3 BS2

The NM_001429.4(EP300):​c.5556_5564delTGCCACTCC​(p.Ala1853_Pro1855del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,886 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (1 hom.)
• Consequence: EP300 NM_001429.4 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.87

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]

ENSG00000232754 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001429.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EP300	NM_001429.4	c.5556_5564delTGCCACTCC	p.Ala1853_Pro1855del	disruptive_inframe_deletion	31/31	ENST00000263253.9	NP_001420.2
EP300	NM_001362843.2	c.5478_5486delTGCCACTCC	p.Ala1827_Pro1829del	disruptive_inframe_deletion	30/30		NP_001349772.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EP300	ENST00000263253.9	c.5556_5564delTGCCACTCC	p.Ala1853_Pro1855del	disruptive_inframe_deletion	31/31	1	NM_001429.4	ENSP00000263253.7
EP300	ENST00000674155.1	c.5478_5486delTGCCACTCC	p.Ala1827_Pro1829del	disruptive_inframe_deletion	30/30			ENSP00000501078.1
ENSG00000232754	ENST00000415054.1	n.82+5795_82+5803delCAGGAGTGG		intron_variant		3
EP300-AS1	ENST00000420537.1	n.224-2444_224-2436delCAGGAGTGG		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461886 Hom.: 1 AF XY: 0.00000688 AC XY: 5 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000629

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 25, 2017

- -

Rubinstein-Taybi syndrome due to EP300 haploinsufficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 16, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 521831). This variant has not been reported in the literature in individuals affected with EP300-related conditions. This variant is not present in population databases (gnomAD no frequency). This variant, c.5556_5564del, results in the deletion of 3 amino acid(s) of the EP300 protein (p.Ala1853_Pro1855del), but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555912151; hg19: chr22-41573263;