rs875989807

Variant names:

• chr22-41178277-TGCAACAGCAGCA-T
• rs875989807
• NM_001429.4:c.6574_6585delCAGCAGCAACAG

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM4 BS2

The NM_001429.4(EP300):​c.6574_6585delCAGCAGCAACAG​(p.Gln2192_Gln2195del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.000147 in 1,613,900 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: EP300 NM_001429.4 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 B:3
• Conservation: PhyloP100: 6.67

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]

ENSG00000232754 (HGNC:):

EP300-AS1 (HGNC:50504): (EP300 antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001429.4.
• BS2: High AC in GnomAd4 at 36 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EP300	NM_001429.4	c.6574_6585delCAGCAGCAACAG	p.Gln2192_Gln2195del	conservative_inframe_deletion	Exon 31 of 31	ENST00000263253.9	NP_001420.2
EP300	NM_001362843.2	c.6496_6507delCAGCAGCAACAG	p.Gln2166_Gln2169del	conservative_inframe_deletion	Exon 30 of 30		NP_001349772.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EP300	ENST00000263253.9	c.6574_6585delCAGCAGCAACAG	p.Gln2192_Gln2195del	conservative_inframe_deletion	Exon 31 of 31	1	NM_001429.4	ENSP00000263253.7
EP300	ENST00000674155.1	c.6496_6507delCAGCAGCAACAG	p.Gln2166_Gln2169del	conservative_inframe_deletion	Exon 30 of 30			ENSP00000501078.1
ENSG00000232754	ENST00000415054.1	n.82+4774_82+4785delTGCTGCTGTTGC		intron_variant	Intron 1 of 2	3
EP300-AS1	ENST00000420537.1	n.224-3465_224-3454delTGCTGCTGTTGC		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152018 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000271 AC: 68 AN: 251352 Hom.: 0 AF XY: 0.000243 AC XY: 33 AN XY: 135862

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00328

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000138 AC: 202 AN: 1461882 Hom.: 0 AF XY: 0.000144 AC XY: 105 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00314

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.000318

Gnomad4 NFE exome AF: 0.0000540

Gnomad4 OTH exome AF: 0.000430

GnomAD4 genome AF: 0.000237 AC: 36 AN: 152018 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74252

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000727 Hom.: 0

Bravo AF: 0.000136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Rubinstein-Taybi syndrome due to EP300 haploinsufficiency Pathogenic:1 Benign:1

Jan 01, 2015

Center for Human Genetics, University of Leuven

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Dec 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

EP300-related disorder Benign:1

Sep 08, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

EP300: BS2 -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs875989807; hg19: chr22-41574281;