22-41125999-A-G

Variant names:

• chr22-41125999-A-G
• rs2230111
• NM_001429.4:c.865A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001429.4(EP300):​c.865A>G​(p.Met289Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00289 in 1,614,186 control chromosomes in the GnomAD database, including 13 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (12 hom.)
• Consequence: EP300 NM_001429.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 1.68
• Publications: 13 publications found

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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008583099).
• BP6: Variant 22-41125999-A-G is Benign according to our data. Variant chr22-41125999-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 316 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.865A>G	p.Met289Val	missense	Exon 3 of 31	NP_001420.2	Q09472
	EP300	NM_001362843.2		c.865A>G	p.Met289Val	missense	Exon 3 of 30	NP_001349772.1	A0A669KB12

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EP300	ENST00000263253.9	TSL:1 MANE Select	c.865A>G	p.Met289Val	missense	Exon 3 of 31	ENSP00000263253.7	Q09472
	EP300	ENST00000916082.1		c.865A>G	p.Met289Val	missense	Exon 3 of 31	ENSP00000586141.1
	EP300	ENST00000715703.1		c.865A>G	p.Met289Val	missense	Exon 3 of 31	ENSP00000520505.1	Q09472

Frequencies

GnomAD3 genomes AF: 0.00208 AC: 316 AN: 152194 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00378

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00206 AC: 518 AN: 251424 AF XY: 0.00221

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.000520

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00120

Gnomad NFE exome AF: 0.00384

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00297 AC: 4348 AN: 1461874 Hom.: 12 Cov.: 31 AF XY: 0.00293 AC XY: 2133 AN XY: 727242

African (AFR) AF: 0.000448 AC: 15 AN: 33480

American (AMR) AF: 0.000425 AC: 19 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39696

South Asian (SAS) AF: 0.000290 AC: 25 AN: 86258

European-Finnish (FIN) AF: 0.00163 AC: 87 AN: 53420

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00365 AC: 4057 AN: 1111998

Other (OTH) AF: 0.00232 AC: 140 AN: 60396

GnomAD4 genome AF: 0.00207 AC: 316 AN: 152312 Hom.: 1 Cov.: 32 AF XY: 0.00205 AC XY: 153 AN XY: 74474

African (AFR) AF: 0.000626 AC: 26 AN: 41566

American (AMR) AF: 0.000980 AC: 15 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00378 AC: 257 AN: 68030

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00322 Hom.: 2

Bravo AF: 0.00192

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00302 AC: 26

ExAC AF: 0.00229 AC: 278

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00382

EpiControl AF: 0.00320

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	not specified (3)
-	-	1	EP300-related disorder (1)
-	-	1	Rubinstein-Taybi syndrome due to EP300 haploinsufficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	15
DANN	Benign	0.90
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.0086	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.7
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.81	N
REVEL	Benign	0.22
Sift	Benign	0.38	T
Sift4G	Benign	0.45	T
Polyphen		0.024	B
Vest4		0.22
MVP		0.73
ClinPred		0.0082	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.24
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs2230111; hg19: chr22-41522003; COSMIC: COSV105840063;