chr22-41166649-A-G
Position:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_001429.4(EP300):c.3857A>G(p.Asn1286Ser) 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 Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
EP300
NM_001429.4 missense
NM_001429.4 missense
Scores
7
10
2
Clinical Significance
Conservation
PhyloP100: 9.08
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 12 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 22-41166649-A-G is Pathogenic according to our data. Variant chr22-41166649-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 378053.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.3857A>G | p.Asn1286Ser | missense_variant | 23/31 | ENST00000263253.9 | |
EP300 | NM_001362843.2 | c.3779A>G | p.Asn1260Ser | missense_variant | 22/30 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EP300 | ENST00000263253.9 | c.3857A>G | p.Asn1286Ser | missense_variant | 23/31 | 1 | NM_001429.4 | P2 | |
EP300 | ENST00000674155.1 | c.3779A>G | p.Asn1260Ser | missense_variant | 22/30 | A2 | |||
EP300 | ENST00000635584.1 | n.182A>G | non_coding_transcript_exon_variant | 3/6 | 4 | ||||
EP300 | ENST00000703544.1 | c.*1777A>G | 3_prime_UTR_variant, NMD_transcript_variant | 22/30 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Rubinstein-Taybi syndrome due to EP300 haploinsufficiency Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2021 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with Rubinstein–Taybi syndrome (PMID: 27648933, 27465822). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 378053). This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with serine at codon 1286 of the EP300 protein (p.Asn1286Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 26, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | May 22, 2022 | The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.61; 3Cnet: 0.39). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000378053). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 27465822, 32827181, 33644862). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 27648933). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | Aug 30, 2021 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Wessex Regional Genetics Laboratory, Salisbury District Hospital | Nov 05, 2019 | - - |
See cases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Sep 03, 2021 | ACMG classification criteria: PS4, PM2, PM6 - |
EP300-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 20, 2023 | The EP300 c.3857A>G variant is predicted to result in the amino acid substitution p.Asn1286Ser. This variant has been reported in multiple individuals with Rubinstein-Taybi syndrome and neurodevelopmental disorders; in most of these individuals, this variant was found to have arise de novo (Fergelot et al 2016. PubMed ID: 27648933; Hamilton MJ et al 2016. PubMed ID: 27465822; Table_S2, Turner TN et al 2019. PubMed ID: 31785789; Cross E et al 2020. PubMed ID: 32827181; Hiraide T et al 2021. PubMed ID: 33644862; Hamilton MJ et al 2016. PubMed ID: 27465822). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 09, 2022 | Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27465822, 32827181, 33644862, 27648933, 31785789) - |
Intellectual disability Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Diagnostic Laboratory, Strasbourg University Hospital | Sep 10, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Gain of phosphorylation at N1286 (P = 0.0117);
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
DS_DG_spliceai
Position offset: -1
DS_DL_spliceai
Position offset: 17
Find out detailed SpliceAI scores and Pangolin per-transcript scores at