22-41146833-A-T

Variant names:

• chr22-41146833-A-T
• rs113214815
• NM_001429.4:c.2131+17A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001429.4(EP300):​c.2131+17A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00231 in 1,608,968 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (31 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (48 hom.)
• Consequence: EP300 NM_001429.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.163
• Publications: 1 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 22-41146833-A-T is Benign according to our data. Variant chr22-41146833-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1200316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.012 (1829/152174) while in subpopulation AFR AF = 0.0423 (1757/41494). AF 95% confidence interval is 0.0407. There are 31 homozygotes in GnomAd4. There are 827 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1829 AD gene.

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.2131+17A>T		intron	N/A	NP_001420.2	Q09472
	EP300	NM_001362843.2		c.2054-1004A>T		intron	N/A	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.2131+17A>T		intron	N/A	ENSP00000263253.7	Q09472
	EP300	ENST00000916082.1		c.2131+17A>T		intron	N/A	ENSP00000586141.1
	EP300	ENST00000715703.1		c.2131+17A>T		intron	N/A	ENSP00000520505.1	Q09472

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1827 AN: 152056 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.0424

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00815

GnomAD2 exomes AF: 0.00284 AC: 698 AN: 245504 AF XY: 0.00207

Gnomad AFR exome AF: 0.0405

Gnomad AMR exome AF: 0.00169

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000118

Gnomad OTH exome AF: 0.000998

GnomAD4 exome AF: 0.00130 AC: 1895 AN: 1456794 Hom.: 48 Cov.: 29 AF XY: 0.00112 AC XY: 813 AN XY: 724882

African (AFR) AF: 0.0473 AC: 1565 AN: 33066

American (AMR) AF: 0.00206 AC: 92 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39394

South Asian (SAS) AF: 0.0000466 AC: 4 AN: 85822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53106

Middle Eastern (MID) AF: 0.000699 AC: 4 AN: 5722

European-Non Finnish (NFE) AF: 0.0000839 AC: 93 AN: 1108736

Other (OTH) AF: 0.00226 AC: 136 AN: 60184

GnomAD4 genome AF: 0.0120 AC: 1829 AN: 152174 Hom.: 31 Cov.: 32 AF XY: 0.0111 AC XY: 827 AN XY: 74406

African (AFR) AF: 0.0423 AC: 1757 AN: 41494

American (AMR) AF: 0.00288 AC: 44 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68008

Other (OTH) AF: 0.00806 AC: 17 AN: 2108

Alfa AF: 0.00639 Hom.: 0

Bravo AF: 0.0139

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Rubinstein-Taybi syndrome due to EP300 haploinsufficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.53
DANN	Benign	0.46
PhyloP100		-0.16
Mutation Taster		=100/0	polymorphism

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: rs113214815; hg19: chr22-41542837;