rs148693910

chr22-41117678-A-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001429.4(EP300):c.586A>G(p.Ile196Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000997 in 1,614,238 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000099 (1 hom.)
• Consequence: EP300 NM_001429.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 2.15

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0728046).
• BP6: Variant 22-41117678-A-G is Benign according to our data. Variant chr22-41117678-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158567.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
• BS2: High AC in GnomAd at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EP300	NM_001429.4	c.586A>G	p.Ile196Val	missense_variant	2/31	ENST00000263253.9
EP300	NM_001362843.2	c.586A>G	p.Ile196Val	missense_variant	2/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EP300	ENST00000263253.9	c.586A>G	p.Ile196Val	missense_variant	2/31	1	NM_001429.4	P2
EP300	ENST00000674155.1	c.586A>G	p.Ile196Val	missense_variant	2/30			A2
EP300	ENST00000703544.1	c.586A>G	p.Ile196Val	missense_variant, NMD_transcript_variant	2/30
EP300	ENST00000703545.1	c.472A>G	p.Ile158Val	missense_variant, NMD_transcript_variant	1/17

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000954 AC: 24 AN: 251466 Hom.: 1 AF XY: 0.000118 AC XY: 16 AN XY: 135910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000105

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000985 AC: 144 AN: 1461892 Hom.: 1 Cov.: 32 AF XY: 0.000107 AC XY: 78 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000764

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152346 Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7 AN XY: 74494

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000162 Hom.: 0

Bravo AF: 0.000117

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Rubinstein-Taybi syndrome due to EP300 haploinsufficiency Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 12, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Nov 08, 2023	- -

EP300-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 20, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2022

EP300: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	18
Dann	Benign	0.85
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	0.89	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.20
Sift	Benign	0.45	T
Sift4G	Benign	1.0	T
Polyphen		0.11	B
Vest4		0.33
MVP		0.82
ClinPred		0.028	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.041
gMVP		0.27

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: rs148693910; hg19: chr22-41513682; COSMIC: COSV105033051; COSMIC: COSV105033051;