16-3741260-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004380.3(CREBBP):c.3983-711T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.483 in 154,112 control chromosomes in the GnomAD database, including 21,436 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 0.48 (21011 hom., cov: 34)
  • Exomes 𝑓: 0.64 (425 hom.)
• Consequence: CREBBP NM_004380.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.73

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.644 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CREBBP	NM_004380.3	c.3983-711T>C		intron_variant		ENST00000262367.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CREBBP	ENST00000262367.10	c.3983-711T>C		intron_variant		1	NM_004380.3	P1

Frequencies

GnomAD3 genomes AF: 0.481 AC: 73199 AN: 152088 Hom.: 21014 Cov.: 34

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.662

Gnomad AMR AF: 0.497

Gnomad ASJ AF: 0.506

Gnomad EAS AF: 0.447

Gnomad SAS AF: 0.508

Gnomad FIN AF: 0.636

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.649

Gnomad OTH AF: 0.501

GnomAD4 exome AF: 0.645 AC: 1229 AN: 1906 Hom.: 425 Cov.: 0 AF XY: 0.671 AC XY: 617 AN XY: 920

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.515

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.667

Gnomad4 SAS exome AF: 0.543

Gnomad4 NFE exome AF: 0.689

Gnomad4 OTH exome AF: 0.727

GnomAD4 genome AF: 0.481 AC: 73201 AN: 152206 Hom.: 21011 Cov.: 34 AF XY: 0.483 AC XY: 35936 AN XY: 74416

Gnomad4 AFR AF: 0.154

Gnomad4 AMR AF: 0.497

Gnomad4 ASJ AF: 0.506

Gnomad4 EAS AF: 0.446

Gnomad4 SAS AF: 0.507

Gnomad4 FIN AF: 0.636

Gnomad4 NFE AF: 0.649

Gnomad4 OTH AF: 0.504

Alfa AF: 0.606 Hom.: 35886

Bravo AF: 0.458

Asia WGS AF: 0.447 AC: 1553 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	5.0
Dann	Benign	0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs129968; hg19: chr16-3791261;