NM_004380.3:c.3983-711T>C

Variant names:

• chr16-3741260-A-G
• rs129968
• NM_004380.3:c.3983-711T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 13 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=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.644 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004380.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CREBBP	NM_004380.3	MANE Select	c.3983-711T>C		intron	N/A	NP_004371.2
	CREBBP	NM_001079846.1		c.3869-711T>C		intron	N/A	NP_001073315.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CREBBP	ENST00000262367.10	TSL:1 MANE Select	c.3983-711T>C		intron	N/A	ENSP00000262367.5
	CREBBP	ENST00000382070.7	TSL:1	c.3869-711T>C		intron	N/A	ENSP00000371502.3
	CREBBP	ENST00000576720.1	TSL:2	n.2209T>C		non_coding_transcript_exon	Exon 1 of 5

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

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AF: 0.515 AC: 207 AN: 402

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.667 AC: 8 AN: 12

South Asian (SAS) AF: 0.543 AC: 50 AN: 92

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.689 AC: 916 AN: 1330

Other (OTH) AF: 0.727 AC: 48 AN: 66

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

African (AFR) AF: 0.154 AC: 6404 AN: 41552

American (AMR) AF: 0.497 AC: 7598 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.506 AC: 1758 AN: 3472

East Asian (EAS) AF: 0.446 AC: 2308 AN: 5172

South Asian (SAS) AF: 0.507 AC: 2448 AN: 4824

European-Finnish (FIN) AF: 0.636 AC: 6732 AN: 10582

Middle Eastern (MID) AF: 0.517 AC: 152 AN: 294

European-Non Finnish (NFE) AF: 0.649 AC: 44133 AN: 68006

Other (OTH) AF: 0.504 AC: 1066 AN: 2114

Alfa AF: 0.586 Hom.: 48426

Bravo AF: 0.458

Asia WGS AF: 0.447 AC: 1553 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.0
DANN	Benign	0.67
PhyloP100		1.7
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: rs129968; hg19: chr16-3791261;