rs28937578

Variant names:

• chr22-41178373-C-A
• rs28937578
• NM_001429.4:c.6662C>A

Your query was ambiguous. Multiple possible variants found:

• chr22-41178373-C-A
• chr22-41178373-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_001429.4(EP300):​c.6662C>A​(p.Pro2221Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2221L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EP300 NM_001429.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.103
• Publications: 4 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-AS1 (HGNC:50504): (EP300 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-41178373-C-A is Pathogenic according to our data. Variant chr22-41178373-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 6881.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2090106). . Strength limited to SUPPORTING due to the PP5.

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.6662C>A	p.Pro2221Gln	missense	Exon 31 of 31	NP_001420.2	Q09472
	EP300	NM_001362843.2		c.6584C>A	p.Pro2195Gln	missense	Exon 30 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.6662C>A	p.Pro2221Gln	missense	Exon 31 of 31	ENSP00000263253.7	Q09472
	EP300	ENST00000916082.1		c.6692C>A	p.Pro2231Gln	missense	Exon 31 of 31	ENSP00000586141.1
	EP300	ENST00000715703.1		c.6662C>A	p.Pro2221Gln	missense	Exon 31 of 31	ENSP00000520505.1	Q09472

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Carcinoma of colon (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	3.5
DANN	Benign	0.68
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.62
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.47	T
M_CAP	Pathogenic	0.64	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.42	N
PhyloP100		0.10
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.17
Sift	Benign	0.60	T
Sift4G	Benign	0.38	T
Polyphen		0.0	B
Vest4		0.25
MutPred		0.25		Loss of loop (P = 0.0153)
MVP		0.66
ClinPred		0.054	T
GERP RS		3.2
Varity_R		0.039
gMVP		0.25
Mutation Taster		=98/2	disease causing (ClinVar)

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: rs28937578; hg19: chr22-41574377; COSMIC: COSV54338224;