rs1555910482

chr22-41162732-TAAAG-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001429.4(EP300):c.3684_3687del(p.Lys1228AsnfsTer48) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EP300 NM_001429.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.09

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 22-41162732-TAAAG-T is Pathogenic according to our data. Variant chr22-41162732-TAAAG-T is described in ClinVar as [Pathogenic]. Clinvar id is 487228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EP300	NM_001429.4	c.3684_3687del	p.Lys1228AsnfsTer48	frameshift_variant	21/31	ENST00000263253.9
EP300	NM_001362843.2	c.3606_3609del	p.Lys1202AsnfsTer48	frameshift_variant	20/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EP300	ENST00000263253.9	c.3684_3687del	p.Lys1228AsnfsTer48	frameshift_variant	21/31	1	NM_001429.4	P2
EP300	ENST00000674155.1	c.3606_3609del	p.Lys1202AsnfsTer48	frameshift_variant	20/30			A2
EP300	ENST00000635584.1	n.9_12del		non_coding_transcript_exon_variant	1/6	4
EP300	ENST00000703544.1	c.*1604_*1607del		3_prime_UTR_variant, NMD_transcript_variant	20/30

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rubinstein-Taybi syndrome due to EP300 haploinsufficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 14, 2017

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in EP300 are known to be pathogenic (PMID: 15706485, 24476420). This variant has not been reported in the literature in individuals with EP300-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Lys1228Asnfs*48) in the EP300 gene. It is expected to result in an absent or disrupted protein product. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1555910482; hg19: chr22-41558736;