rs1046088

Positions:

• chr22-41178379-A-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001429.4(EP300):​c.6668A>C​(p.Gln2223Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0304 in 1,614,146 control chromosomes in the GnomAD database, including 883 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q2223K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.023 (59 hom., cov: 32)
  • Exomes 𝑓: 0.031 (824 hom.)
• Consequence: EP300 NM_001429.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 3.35

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 Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 4 uncertain in NM_001429.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0054445565).
• BP6: Variant 22-41178379-A-C is Benign according to our data. Variant chr22-41178379-A-C is described in ClinVar as [Benign]. Clinvar id is 93744.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0234 (3563/152272) while in subpopulation NFE AF= 0.0357 (2427/68010). AF 95% confidence interval is 0.0345. There are 59 homozygotes in gnomad4. There are 1701 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3563 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EP300	NM_001429.4	c.6668A>C	p.Gln2223Pro	missense_variant	31/31	ENST00000263253.9
EP300	NM_001362843.2	c.6590A>C	p.Gln2197Pro	missense_variant	30/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EP300	ENST00000263253.9	c.6668A>C	p.Gln2223Pro	missense_variant	31/31	1	NM_001429.4	P2
	ENST00000415054.1	n.82+4684T>G		intron_variant, non_coding_transcript_variant		3
EP300-AS1	ENST00000420537.1	n.224-3555T>G		intron_variant, non_coding_transcript_variant		3
EP300	ENST00000674155.1	c.6590A>C	p.Gln2197Pro	missense_variant	30/30			A2

Frequencies

GnomAD3 genomes AF: 0.0234 AC: 3563 AN: 152154 Hom.: 59 Cov.: 32

Gnomad AFR AF: 0.00610

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.0169

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0401

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0357

Gnomad OTH AF: 0.0216

GnomAD3 exomes AF: 0.0238 AC: 5967 AN: 251224 Hom.: 91 AF XY: 0.0235 AC XY: 3185 AN XY: 135790

Gnomad AFR exome AF: 0.00511

Gnomad AMR exome AF: 0.0141

Gnomad ASJ exome AF: 0.0283

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.00294

Gnomad FIN exome AF: 0.0410

Gnomad NFE exome AF: 0.0348

Gnomad OTH exome AF: 0.0294

GnomAD4 exome AF: 0.0311 AC: 45443 AN: 1461874 Hom.: 824 Cov.: 32 AF XY: 0.0303 AC XY: 22043 AN XY: 727236

Gnomad4 AFR exome AF: 0.00490

Gnomad4 AMR exome AF: 0.0145

Gnomad4 ASJ exome AF: 0.0261

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00326

Gnomad4 FIN exome AF: 0.0468

Gnomad4 NFE exome AF: 0.0354

Gnomad4 OTH exome AF: 0.0290

GnomAD4 genome AF: 0.0234 AC: 3563 AN: 152272 Hom.: 59 Cov.: 32 AF XY: 0.0228 AC XY: 1701 AN XY: 74452

Gnomad4 AFR AF: 0.00609

Gnomad4 AMR AF: 0.0169

Gnomad4 ASJ AF: 0.0291

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.0401

Gnomad4 NFE AF: 0.0357

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.0311 Hom.: 155

Bravo AF: 0.0214

TwinsUK AF: 0.0332 AC: 123

ALSPAC AF: 0.0332 AC: 128

ESP6500AA AF: 0.00567 AC: 25

ESP6500EA AF: 0.0363 AC: 312

ExAC AF: 0.0241 AC: 2925

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0350

EpiControl AF: 0.0299

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 07, 2013	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Rubinstein-Taybi syndrome due to EP300 haploinsufficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 11, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	16
DANN	Benign	0.91
DEOGEN2	Uncertain	0.59	D
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.082
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	0.97	D
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.18
Sift	Benign	0.17	T
Sift4G	Benign	0.14	T
Polyphen		0.0	B
Vest4		0.11
ClinPred		0.031	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.37
gMVP		0.37

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: rs1046088; hg19: chr22-41574383; COSMIC: COSV54331579; COSMIC: COSV54331579;