NM_001429.4:c.586A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

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. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I196T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000099 ( 1 hom. )

Consequence

EP300
NM_001429.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 2.15

Publications

7 publications found

Variant links:

COSMIC-nc: COSV105033051

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 Gene-Disease associations (from GenCC):

Rubinstein-Taybi syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: Illumina
Rubinstein-Taybi syndrome due to EP300 haploinsufficiency
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen
retinitis pigmentosa
Inheritance: AD Classification: LIMITED Submitted by: G2P

EP300 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 158567.

BS2

High AC in GnomAd4 at 17 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001429.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EP300	NM_001429.4	MANE Select	c.586A>G	p.Ile196Val	missense	Exon 2 of 31	NP_001420.2	Q09472
	EP300	NM_001362843.2		c.586A>G	p.Ile196Val	missense	Exon 2 of 30	NP_001349772.1	A0A669KB12

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EP300	ENST00000263253.9	TSL:1 MANE Select	c.586A>G	p.Ile196Val	missense	Exon 2 of 31	ENSP00000263253.7	Q09472
EP300	ENST00000916082.1		c.586A>G	p.Ile196Val	missense	Exon 2 of 31	ENSP00000586141.1
EP300	ENST00000715703.1		c.586A>G	p.Ile196Val	missense	Exon 2 of 31	ENSP00000520505.1	Q09472

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0000954

AC:

AN:

251466

AF XY:

0.000118

show subpopulations

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 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.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.000246

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00468

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000764

AC:

AN:

1112010

Other (OTH)

AF:

0.0000993

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000112

AC:

AN:

152346

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41580

American (AMR)

AF:

0.0000654

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68034

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000188

Hom.:

Bravo

AF:

0.000117

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Rubinstein-Taybi syndrome due to EP300 haploinsufficiency (2)

EP300-related disorder (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.36

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.26

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.78

M_CAP

Benign

0.017

MetaRNN

Benign

0.073

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.69

PhyloP100

2.2

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.050

REVEL

Benign

0.20

Sift

Benign

0.45

Sift4G

Benign

1.0

Polyphen

0.11

Vest4

0.33

MVP

0.82

ClinPred

0.028

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.041

gMVP

0.27

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over