rs1555909697

chr22-41152276-TAAAAG-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001429.4(EP300):c.3070_3074del(p.Lys1024GlyfsTer63) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: EP300 NM_001429.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.04

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-41152276-TAAAAG-T is Pathogenic according to our data. Variant chr22-41152276-TAAAAG-T is described in ClinVar as [Pathogenic]. Clinvar id is 487227.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EP300	NM_001429.4	c.3070_3074del	p.Lys1024GlyfsTer63	frameshift_variant	16/31	ENST00000263253.9
EP300	NM_001362843.2	c.2992_2996del	p.Lys998GlyfsTer63	frameshift_variant	15/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EP300	ENST00000263253.9	c.3070_3074del	p.Lys1024GlyfsTer63	frameshift_variant	16/31	1	NM_001429.4	P2
EP300	ENST00000674155.1	c.2992_2996del	p.Lys998GlyfsTer63	frameshift_variant	15/30			A2
EP300	ENST00000703544.1	c.*990_*994del		3_prime_UTR_variant, NMD_transcript_variant	15/30
EP300	ENST00000703545.1	c.*1440_*1444del		3_prime_UTR_variant, NMD_transcript_variant	14/17

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rubinstein-Taybi syndrome due to EP300 haploinsufficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 14, 2017

This sequence change creates a premature translational stop signal (p.Lys1024Glyfs*63) in the EP300 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with EP300-related disease. Loss-of-function variants in EP300 are known to be pathogenic (PMID: 15706485, 24476420). For these reasons, this variant has been classified as Pathogenic. -

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: rs1555909697; hg19: chr22-41548280;