22-41176250-T-G

Position:

• chr22-41176250-T-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PM5 PP3_Moderate PP5_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F1595I) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: EP300 NM_001429.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13 O:1
• 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]

(HGNC:):

EP300-AS1 (HGNC:50504): (EP300 antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-41176250-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 1685771.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EP300	NM_001429.4	c.4783T>G	p.Phe1595Val	missense_variant	30/31	ENST00000263253.9
EP300	NM_001362843.2	c.4705T>G	p.Phe1569Val	missense_variant	29/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EP300	ENST00000263253.9	c.4783T>G	p.Phe1595Val	missense_variant	30/31	1	NM_001429.4	P2
	ENST00000415054.1	n.83-6669A>C		intron_variant, non_coding_transcript_variant		3
EP300-AS1	ENST00000420537.1	n.224-1426A>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rubinstein-Taybi syndrome due to EP300 haploinsufficiency Pathogenic:7

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 26, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Jun 21, 2019	- -
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	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 -

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

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.62		Gain of sheet (P = 0.0827);
MVP		0.95
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.94
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

Other links and lift over

dbSNP: rs1057517732; hg19: chr22-41572254;