16-3784315-T-C

Variant names:

• chr16-3784315-T-C
• rs130024
• NM_004380.3:c.1331-1389A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_004380.3(CREBBP):​c.1331-1389A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0512 in 152,284 control chromosomes in the GnomAD database, including 284 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 0.051 (284 hom., cov: 32)
• Consequence: CREBBP NM_004380.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.419
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0699 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CREBBP	NM_004380.3	c.1331-1389A>G		intron_variant	Intron 5 of 30	ENST00000262367.10	NP_004371.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CREBBP	ENST00000262367.10	c.1331-1389A>G		intron_variant	Intron 5 of 30	1	NM_004380.3	ENSP00000262367.5
CREBBP	ENST00000382070.7	c.1217-1389A>G		intron_variant	Intron 4 of 29	1		ENSP00000371502.3
CREBBP	ENST00000635753.1	n.64-1389A>G		intron_variant	Intron 1 of 1	5
CREBBP	ENST00000636002.1	n.43+158A>G		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes AF: 0.0512 AC: 7794 AN: 152166 Hom.: 284 Cov.: 32

Gnomad AFR AF: 0.0121

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.0426

Gnomad ASJ AF: 0.0925

Gnomad EAS AF: 0.00576

Gnomad SAS AF: 0.0703

Gnomad FIN AF: 0.0800

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0716

Gnomad OTH AF: 0.0497

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

GnomAD4 genome AF: 0.0512 AC: 7791 AN: 152284 Hom.: 284 Cov.: 32 AF XY: 0.0508 AC XY: 3783 AN XY: 74462

African (AFR) AF: 0.0121 AC: 501 AN: 41576

American (AMR) AF: 0.0425 AC: 650 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0925 AC: 321 AN: 3470

East Asian (EAS) AF: 0.00578 AC: 30 AN: 5194

South Asian (SAS) AF: 0.0710 AC: 343 AN: 4832

European-Finnish (FIN) AF: 0.0800 AC: 848 AN: 10598

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0716 AC: 4866 AN: 68002

Other (OTH) AF: 0.0491 AC: 104 AN: 2116

Alfa AF: 0.0624 Hom.: 422

Bravo AF: 0.0455

Asia WGS AF: 0.0410 AC: 142 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	15
DANN	Benign	0.83
PhyloP100		0.42
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs130024; hg19: chr16-3834316;