16-3751725-C-G

Position:

• chr16-3751725-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_004380.3(CREBBP):​c.3779+1G>C variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CREBBP NM_004380.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.57

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 Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.010915541 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.5, offset of 29, new splice context is: gggGTgagg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-3751725-C-G is Pathogenic according to our data. Variant chr16-3751725-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 975524.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CREBBP	NM_004380.3	c.3779+1G>C		splice_donor_variant, intron_variant		ENST00000262367.10	NP_004371.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CREBBP	ENST00000262367.10	c.3779+1G>C		splice_donor_variant, intron_variant		1	NM_004380.3	ENSP00000262367.5
CREBBP	ENST00000382070.7	c.3665+1G>C		splice_donor_variant, intron_variant		1		ENSP00000371502.3
CREBBP	ENST00000570939.2	c.2414+1G>C		splice_donor_variant, intron_variant		5		ENSP00000461002.2
CREBBP	ENST00000573517.6	c.83+1G>C		splice_donor_variant, intron_variant		5		ENSP00000460474.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Rubinstein-Taybi syndrome due to CREBBP mutations Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	Jan 01, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Jun 12, 2020	The c.3779+1G>C canonical splice site variant identified in the CREBBP gene has not been reported in the literature. A de novo allelic variant c.3779+1G>A has been reported in anindividual with intellectual disability, short stature, dysmorphic features, but no broad thumbs or great toes as usually seen in Rubinstein-Taybi syndrome [PMID: 27165009] and another de novo allelic variant c.3779+1G>T has been reported in an individual with classical Rubinstein-Taybi syndrome phenotype [PMID: 29132461]. The c.3779+1G>C splice site variant is not reported in gnomAD database indicating this is a rare allele and predicted to damage the canonical splice donor site in intron 20, leads to skipping of exon 20 resulting in-frame deletion of 81 bp in the CREBBP gene [PMID: 27165009]. At the protein level, the deletion of 27 amino acids partially deletes the DUF902 domain which is localized in the histone acetyltransferase (HAT) domain. As most missense mutations found in Rubinstein-Taybi syndrome are clustered in the HAT domain, it was suggested that loss of HAT activity may be sufficient to cause Rubinstein-Taybi syndrome [PMID: 27165009]. Based on the available evidence, the variant c.3779+1G>C in the CREBBP gene is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		5.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587783483; hg19: chr16-3801726;