chr22-41172557-T-G

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

Scores

16
1
2

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.93
Variant links:
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]

Genome browser will be placed here

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
EP300NM_001429.4 linkuse as main transcriptc.4511T>G p.Phe1504Cys missense_variant 28/31 ENST00000263253.9 NP_001420.2
EP300NM_001362843.2 linkuse as main transcriptc.4433T>G p.Phe1478Cys missense_variant 27/30 NP_001349772.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
EP300ENST00000263253.9 linkuse as main transcriptc.4511T>G p.Phe1504Cys missense_variant 28/311 NM_001429.4 ENSP00000263253 P2
ENST00000415054.1 linkuse as main transcriptn.83-2976A>C intron_variant, non_coding_transcript_variant 3
EP300ENST00000674155.1 linkuse as main transcriptc.4433T>G p.Phe1478Cys missense_variant 27/30 ENSP00000501078 A2
EP300ENST00000703544.1 linkuse as main transcriptc.*2431T>G 3_prime_UTR_variant, NMD_transcript_variant 27/30 ENSP00000515365

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
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 submitterresearchFundacion Rioja Salud, Center for Biomedical Research (CIBIR)Jul 01, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.54
D
BayesDel_noAF
Pathogenic
0.54
CADD
Uncertain
25
DANN
Benign
0.97
DEOGEN2
Pathogenic
0.94
D
Eigen
Pathogenic
0.92
Eigen_PC
Pathogenic
0.88
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D
M_CAP
Pathogenic
0.46
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
2.9
M
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.94
D
PROVEAN
Pathogenic
-7.9
D
REVEL
Pathogenic
0.97
Sift
Uncertain
0.019
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.90
MutPred
0.92
Loss of stability (P = 0.0819);
MVP
0.98
ClinPred
1.0
D
GERP RS
6.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.85
gMVP
0.92

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1114167306; hg19: chr22-41568561; API