22-41166649-A-T

Position:

• chr22-41166649-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_001429.4(EP300):​c.3857A>T​(p.Asn1286Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1286S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EP300 NM_001429.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.08

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-41166649-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 378053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EP300	NM_001429.4	c.3857A>T	p.Asn1286Ile	missense_variant	23/31	ENST00000263253.9
EP300	NM_001362843.2	c.3779A>T	p.Asn1260Ile	missense_variant	22/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EP300	ENST00000263253.9	c.3857A>T	p.Asn1286Ile	missense_variant	23/31	1	NM_001429.4	P2
EP300	ENST00000674155.1	c.3779A>T	p.Asn1260Ile	missense_variant	22/30			A2
EP300	ENST00000635584.1	n.182A>T		non_coding_transcript_exon_variant	3/6	4
EP300	ENST00000703544.1	c.*1777A>T		3_prime_UTR_variant, NMD_transcript_variant	22/30

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	3.2	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-8.8	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.019	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.50		Loss of methylation at K1291 (P = 0.0463);
MVP		0.86
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.79
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555910821; hg19: chr22-41562653;