22-41176250-T-G
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_001429.4(EP300):c.4783T>G(p.Phe1595Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
EP300
NM_001429.4 missense
NM_001429.4 missense
Scores
15
3
1
Clinical Significance
Conservation
PhyloP100: 8.02
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
MetaRNN computational evidence supports a deleterious effect, 0.933
PP5
Variant 22-41176250-T-G is Pathogenic according to our data. Variant chr22-41176250-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-41176250-T-G is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461884Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727240
GnomAD4 exome
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2
AN:
1461884
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Cov.:
31
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AC XY:
1
AN XY:
727240
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
Bravo
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:13Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Rubinstein-Taybi syndrome due to EP300 haploinsufficiency Pathogenic:7
Pathogenic, no assertion criteria provided | clinical testing | Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals | Dec 11, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 01, 2023 | This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1595 of the EP300 protein (p.Phe1595Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Rubinstein-Taybi syndrome (PMID: 27465822, 29133209). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 372363). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt EP300 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Feb 20, 2024 | PS4, PM2, PP3, PP5 - The variant has been reported in ClinVar as Pathogenic by other laboratories (Variation ID 372363). This variant has been previously reported as causative for EP300-related l disorders (PMID:29133209). - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion, Medical Genetics | Oct 02, 2021 | The variant has been previously reported as de novoo in a similarly affected individual (PMID: 27465822, PS2) The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.953, 3Cnet: 0.763, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 17, 2023 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Rubinstein-Taybi syndrome 2 (RSTS; MIM#613684) and Menke-Hennekam syndrome 2 (MHS2; MIM#618333). Additionally, dominant negative is a suggested mechanism (PMIDs: 20301699, 24381114). Variants reported to cause RSTS are found throughout the protein, whereas of the few variants reported to cause MHS, all were located in exon 31 (PMID: 29460469). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Clinical features and developmental outcomes vary considerably between individuals with RSTS, with rare reports of pathogenic variants inherited from asymptomatic or mildly affected parents (PMID: 20301699). (I) 0200 - Variant is predicted to result in a missense amino acid change from phenylalanine to valine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated histone acetylation protein (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic and likely pathogenic, and has been observed in individuals with Rubinstein-Taybi syndrome. In at least two of these individuals, the variant was confirmed de novo (ClinVar, PMID: 29133209). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | Jun 21, 2019 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 26, 2019 | - - |
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 09, 2016 | A pathogenic variant has been identified in the EP300 gene. The F1595V variant has been identified as a de novo variant with confirmed parentage in multiple unrelated individuals with developmental delay and dysmorphic features who were previously tested at GeneDx. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The F1595V variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts the F1595V variant is probably damaging to the protein structure/function. Therefore, the presence of this pathogenic variant is consistent with a diagnosis of Rubinstein-Taybi syndrome - |
Likely pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 31, 2021 | - - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 02, 2017 | - - |
EP300-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 10, 2022 | The EP300 c.4783T>G variant is predicted to result in the amino acid substitution p.Phe1595Val. This variant was reported to be a de novo event in multiple individuals with Rubinstein–Taybi syndrome (Table S3 - Retterer et al. 2016. PubMed ID: 26633542; Hamilton et al. 2016. PubMed ID: 27465822; Costain et al. 2017. PubMed ID: 29133209; Lecoquierre et al. 2019. PubMed ID: 31036916; Welters et al. 2019. PubMed ID: 31137009). 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. - |
Multiple congenital anomalies Other:1
not provided, no classification provided | clinical testing | Costain lab, The Hospital for Sick Children | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of sheet (P = 0.0827);
MVP
ClinPred
D
GERP RS
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