rs20552

chr22-41155035-T-Achr22-41155035-T-Cchr22-41155035-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001429.4(EP300):c.3183T>A(p.Thr1061=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.636 in 1,612,840 control chromosomes in the GnomAD database, including 329,576 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (28740 hom., cov: 31)
  • Exomes 𝑓: 0.64 (300836 hom.)
• Consequence: EP300 NM_001429.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.557

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 22-41155035-T-A is Benign according to our data. Variant chr22-41155035-T-A is described in ClinVar as [Benign]. Clinvar id is 93738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-41155035-T-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.557 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.788 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EP300	NM_001429.4	c.3183T>A	p.Thr1061=	synonymous_variant	17/31	ENST00000263253.9
EP300	NM_001362843.2	c.3105T>A	p.Thr1035=	synonymous_variant	16/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EP300	ENST00000263253.9	c.3183T>A	p.Thr1061=	synonymous_variant	17/31	1	NM_001429.4	P2
EP300	ENST00000674155.1	c.3105T>A	p.Thr1035=	synonymous_variant	16/30			A2
EP300	ENST00000703544.1	c.*1103T>A		3_prime_UTR_variant, NMD_transcript_variant	16/30
EP300	ENST00000703545.1	c.*1553T>A		3_prime_UTR_variant, NMD_transcript_variant	15/17

Frequencies

GnomAD3 genomes AF: 0.609 AC: 92405 AN: 151824 Hom.: 28721 Cov.: 31

Gnomad AFR AF: 0.506

Gnomad AMI AF: 0.733

Gnomad AMR AF: 0.746

Gnomad ASJ AF: 0.624

Gnomad EAS AF: 0.808

Gnomad SAS AF: 0.697

Gnomad FIN AF: 0.594

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.618

Gnomad OTH AF: 0.639

GnomAD3 exomes AF: 0.665 AC: 167229 AN: 251460 Hom.: 56995 AF XY: 0.660 AC XY: 89755 AN XY: 135904

Gnomad AFR exome AF: 0.503

Gnomad AMR exome AF: 0.831

Gnomad ASJ exome AF: 0.625

Gnomad EAS exome AF: 0.812

Gnomad SAS exome AF: 0.682

Gnomad FIN exome AF: 0.607

Gnomad NFE exome AF: 0.624

Gnomad OTH exome AF: 0.656

GnomAD4 exome AF: 0.639 AC: 933071 AN: 1460898 Hom.: 300836 Cov.: 46 AF XY: 0.639 AC XY: 464575 AN XY: 726798

Gnomad4 AFR exome AF: 0.492

Gnomad4 AMR exome AF: 0.821

Gnomad4 ASJ exome AF: 0.622

Gnomad4 EAS exome AF: 0.799

Gnomad4 SAS exome AF: 0.678

Gnomad4 FIN exome AF: 0.610

Gnomad4 NFE exome AF: 0.629

Gnomad4 OTH exome AF: 0.640

GnomAD4 genome AF: 0.609 AC: 92460 AN: 151942 Hom.: 28740 Cov.: 31 AF XY: 0.615 AC XY: 45655 AN XY: 74246

Gnomad4 AFR AF: 0.506

Gnomad4 AMR AF: 0.747

Gnomad4 ASJ AF: 0.624

Gnomad4 EAS AF: 0.808

Gnomad4 SAS AF: 0.697

Gnomad4 FIN AF: 0.594

Gnomad4 NFE AF: 0.618

Gnomad4 OTH AF: 0.633

Alfa AF: 0.615 Hom.: 9393

Bravo AF: 0.619

Asia WGS AF: 0.689 AC: 2394 AN: 3478

EpiCase AF: 0.625

EpiControl AF: 0.626

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 10, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

Rubinstein-Taybi syndrome due to EP300 haploinsufficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

Menke-Hennekam syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 20, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
Cadd	Benign	0.43
Dann	Benign	0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs20552; hg19: chr22-41551039; COSMIC: COSV54326782; COSMIC: COSV54326782;