rs3025684

chr16-3745362-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004380.3(CREBBP):c.3837-8C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0488 in 1,613,116 control chromosomes in the GnomAD database, including 10,174 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (4405 hom., cov: 33)
  • Exomes 𝑓: 0.038 (5769 hom.)
• Consequence: CREBBP NM_004380.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00007547
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.88

Genes affected

CREBBP (HGNC:2348): (CREB binding protein) This gene is ubiquitously expressed and is involved in the transcriptional coactivation of many different transcription factors. First isolated as a nuclear protein that binds to cAMP-response element binding protein (CREB), this gene is now known to play critical roles in embryonic development, growth control, and homeostasis by coupling chromatin remodeling to transcription factor recognition. The protein encoded by this gene has intrinsic histone acetyltransferase activity and also acts as a scaffold to stabilize additional protein interactions with the transcription complex. This protein acetylates both histone and non-histone proteins. This protein shares regions of very high sequence similarity with protein p300 in its bromodomain, cysteine-histidine-rich regions, and histone acetyltransferase domain. Mutations in this gene cause Rubinstein-Taybi syndrome (RTS). Chromosomal translocations involving this gene have been associated with acute myeloid leukemia. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 16-3745362-G-A is Benign according to our data. Variant chr16-3745362-G-A is described in ClinVar as [Benign]. Clinvar id is 95045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.438 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CREBBP	NM_004380.3	c.3837-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000262367.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CREBBP	ENST00000262367.10	c.3837-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_004380.3	P1

Frequencies

GnomAD3 genomes AF: 0.149 AC: 22676 AN: 152022 Hom.: 4379 Cov.: 33

Gnomad AFR AF: 0.443

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0736

Gnomad ASJ AF: 0.0841

Gnomad EAS AF: 0.205

Gnomad SAS AF: 0.139

Gnomad FIN AF: 0.00349

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0129

Gnomad OTH AF: 0.125

GnomAD3 exomes AF: 0.0774 AC: 19369 AN: 250330 Hom.: 2469 AF XY: 0.0726 AC XY: 9824 AN XY: 135340

Gnomad AFR exome AF: 0.461

Gnomad AMR exome AF: 0.0381

Gnomad ASJ exome AF: 0.0724

Gnomad EAS exome AF: 0.219

Gnomad SAS exome AF: 0.131

Gnomad FIN exome AF: 0.00301

Gnomad NFE exome AF: 0.0142

Gnomad OTH exome AF: 0.0517

GnomAD4 exome AF: 0.0383 AC: 55987 AN: 1460976 Hom.: 5769 Cov.: 31 AF XY: 0.0397 AC XY: 28857 AN XY: 726750

Gnomad4 AFR exome AF: 0.465

Gnomad4 AMR exome AF: 0.0428

Gnomad4 ASJ exome AF: 0.0749

Gnomad4 EAS exome AF: 0.192

Gnomad4 SAS exome AF: 0.128

Gnomad4 FIN exome AF: 0.00410

Gnomad4 NFE exome AF: 0.0118

Gnomad4 OTH exome AF: 0.0693

GnomAD4 genome AF: 0.150 AC: 22748 AN: 152140 Hom.: 4405 Cov.: 33 AF XY: 0.147 AC XY: 10919 AN XY: 74412

Gnomad4 AFR AF: 0.444

Gnomad4 AMR AF: 0.0735

Gnomad4 ASJ AF: 0.0841

Gnomad4 EAS AF: 0.205

Gnomad4 SAS AF: 0.138

Gnomad4 FIN AF: 0.00349

Gnomad4 NFE AF: 0.0129

Gnomad4 OTH AF: 0.123

Alfa AF: 0.0875 Hom.: 1130

Bravo AF: 0.170

Asia WGS AF: 0.186 AC: 648 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 18, 2013	- -

Rubinstein-Taybi syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
Cadd	Benign	8.8
Dann	Benign	0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000075
dbscSNV1_RF	Benign	0.050
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: rs3025684; hg19: chr16-3795363; COSMIC: COSV52117713; COSMIC: COSV52117713;