22-41149957-T-C

Position:

chr22-41149957-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000263253.9(EP300):c.2576T>C(p.Ile859Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000924 in 1,612,184 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00070 ( 2 hom., cov: 31)

Exomes 𝑓: 0.00095 ( 42 hom. )

Consequence

EP300
ENST00000263253.9 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: 2.00

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]

EP300 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0050047934).

BP6

Variant 22-41149957-T-C is Benign according to our data. Variant chr22-41149957-T-C is described in ClinVar as [Benign]. Clinvar id is 134040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000947 (1384/1461682) while in subpopulation AMR AF= 0.03 (1342/44716). AF 95% confidence interval is 0.0287. There are 42 homozygotes in gnomad4_exome. There are 557 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 106 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EP300	NM_001429.4 linkuse as main transcript	c.2576T>C	p.Ile859Thr	missense_variant	14/31	ENST00000263253.9	NP_001420.2
EP300	NM_001362843.2 linkuse as main transcript	c.2498T>C	p.Ile833Thr	missense_variant	13/30		NP_001349772.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
EP300	ENST00000263253.9 linkuse as main transcript	c.2576T>C	p.Ile859Thr	missense_variant	14/31	1	NM_001429.4	ENSP00000263253	P2
EP300	ENST00000674155.1 linkuse as main transcript	c.2498T>C	p.Ile833Thr	missense_variant	13/30			ENSP00000501078	A2
EP300	ENST00000703544.1 linkuse as main transcript	c.*496T>C		3_prime_UTR_variant, NMD_transcript_variant	13/30			ENSP00000515365
EP300	ENST00000703545.1 linkuse as main transcript	c.*946T>C		3_prime_UTR_variant, NMD_transcript_variant	12/17			ENSP00000515366

Frequencies

GnomAD3 genomes

AF:

0.000705

AC:

106

AN:

150382

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00676

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000443

Gnomad OTH

AF:

0.000484

GnomAD3 exomes

AF:

0.00506

AC:

1271

AN:

251084

Hom.:

AF XY:

0.00365

AC XY:

496

AN XY:

135718

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0364

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.000947

AC:

1384

AN:

1461682

Hom.:

Cov.:

AF XY:

0.000766

AC XY:

557

AN XY:

727138

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0300

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:

0.0000180

Gnomad4 OTH exome

AF:

0.000281

GnomAD4 genome

AF:

0.000704

AC:

106

AN:

150502

Hom.:

Cov.:

AF XY:

0.000681

AC XY:

AN XY:

73450

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00675

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000443

Gnomad4 OTH

AF:

0.000480

Alfa

AF:

0.000162

Hom.:

Bravo

AF:

0.00232

ExAC

AF:

0.00392

AC:

476

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2Other:1

Benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 05, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 08, 2015	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Rubinstein-Taybi syndrome due to EP300 haploinsufficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 10, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.81

DEOGEN2

Benign

0.35

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.60

MetaRNN

Benign

0.0050

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.69

MutationTaster

Benign

0.92

PrimateAI

Uncertain

0.52

PROVEAN

Benign

0.83

REVEL

Benign

0.13

Sift

Benign

0.62

Sift4G

Benign

0.58

Polyphen

0.0

Vest4

0.24

MVP

0.68

ClinPred

0.015

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.034

gMVP

0.083

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over