chr22-41172557-T-G
Position:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate
The NM_001429.4(EP300):c.4511T>G(p.Phe1504Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Consequence
EP300
NM_001429.4 missense
NM_001429.4 missense
Scores
16
1
2
Clinical Significance
Conservation
PhyloP100: 7.93
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM1
In a mutagenesis_site Abolished acetyltransferase activity. (size 0) in uniprot entity EP300_HUMAN
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.987
PP5
Variant 22-41172557-T-G is Pathogenic according to our data. Variant chr22-41172557-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 253314.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-41172557-T-G is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
EP300 | NM_001429.4 | c.4511T>G | p.Phe1504Cys | missense_variant | 28/31 | ENST00000263253.9 | NP_001420.2 | |
EP300 | NM_001362843.2 | c.4433T>G | p.Phe1478Cys | missense_variant | 27/30 | NP_001349772.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
EP300 | ENST00000263253.9 | c.4511T>G | p.Phe1504Cys | missense_variant | 28/31 | 1 | NM_001429.4 | ENSP00000263253 | P2 | |
ENST00000415054.1 | n.83-2976A>C | intron_variant, non_coding_transcript_variant | 3 | |||||||
EP300 | ENST00000674155.1 | c.4433T>G | p.Phe1478Cys | missense_variant | 27/30 | ENSP00000501078 | A2 | |||
EP300 | ENST00000703544.1 | c.*2431T>G | 3_prime_UTR_variant, NMD_transcript_variant | 27/30 | ENSP00000515365 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Rubinstein-Taybi syndrome due to EP300 haploinsufficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Fundacion Rioja Salud, Center for Biomedical Research (CIBIR) | Jul 01, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Benign
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Loss of stability (P = 0.0819);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at