rs11076783

Variant names:

• chr16-3732704-C-T
• rs11076783
• NM_004380.3:c.4729-767G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004380.3(CREBBP):​c.4729-767G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 151,544 control chromosomes in the GnomAD database, including 5,061 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.19 (5061 hom., cov: 31)
• Consequence: CREBBP NM_004380.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.36
• Publications: 3 publications found

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]

CREBBP Gene-Disease associations (from GenCC):

• Rubinstein-Taybi syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Illumina
• Rubinstein-Taybi syndrome due to CREBBP mutations

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• Menke-Hennekam syndrome 1

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.45 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CREBBP	NM_004380.3	c.4729-767G>A		intron_variant	Intron 28 of 30	ENST00000262367.10	NP_004371.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CREBBP	ENST00000262367.10	c.4729-767G>A		intron_variant	Intron 28 of 30	1	NM_004380.3	ENSP00000262367.5
CREBBP	ENST00000382070.7	c.4615-767G>A		intron_variant	Intron 27 of 29	1		ENSP00000371502.3
CREBBP	ENST00000571763.5	n.519-767G>A		intron_variant	Intron 2 of 2	2
CREBBP	ENST00000576720.1	n.3552-767G>A		intron_variant	Intron 4 of 4	2

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29457 AN: 151426 Hom.: 5036 Cov.: 31

Gnomad AFR AF: 0.455

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.134

Gnomad EAS AF: 0.260

Gnomad SAS AF: 0.244

Gnomad FIN AF: 0.0581

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.0689

Gnomad OTH AF: 0.180

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.195 AC: 29530 AN: 151544 Hom.: 5061 Cov.: 31 AF XY: 0.194 AC XY: 14339 AN XY: 74054

African (AFR) AF: 0.456 AC: 18791 AN: 41234

American (AMR) AF: 0.129 AC: 1957 AN: 15206

Ashkenazi Jewish (ASJ) AF: 0.134 AC: 463 AN: 3464

East Asian (EAS) AF: 0.260 AC: 1325 AN: 5090

South Asian (SAS) AF: 0.244 AC: 1166 AN: 4782

European-Finnish (FIN) AF: 0.0581 AC: 611 AN: 10514

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.0689 AC: 4680 AN: 67946

Other (OTH) AF: 0.177 AC: 373 AN: 2104

Alfa AF: 0.143 Hom.: 401

Bravo AF: 0.213

Asia WGS AF: 0.254 AC: 884 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.42
DANN	Benign	0.41
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

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: rs11076783; hg19: chr16-3782705;