rs587783483

Positions:

• chr16-3751725-C-A
• chr16-3751725-C-G
• chr16-3751725-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_004380.3(CREBBP):​c.3779+1G>T 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CREBBP NM_004380.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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 Pathogenic. Variant got 12 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-A is Pathogenic according to our data. Variant chr16-3751725-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 694820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CREBBP-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 11, 2022

The CREBBP c.3779+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been previously reported in individuals with Rubinstein-Taybi syndrome (Li et al. 2017. PubMed ID: 29132461; Cross et al. 2020. PubMed ID: 32827181), and in an individual with developmental disorder (reported with genomic position 3801726 in Table S2, Turner et al. 2019. PubMed ID: 31785789). An alternate nucleotide change (c.3779+1G>A) has also been reported in a large cohort of individuals with Rubinstein-Taibi syndrome (Cross et al. 2020. PubMed ID: 32827181). The c.3779+1G>T variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants that disrupt the consensus splice donor site in CREBBP are expected to be pathogenic. This variant is interpreted as pathogenic. -

Rubinstein-Taybi syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 10, 2023

For these reasons, this variant has been classified as Pathogenic. This sequence change affects a donor splice site in intron 20 of the CREBBP gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CREBBP are known to be pathogenic (PMID: 17052327, 18792986). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with Rubinstein-Taybi syndrome (PMID: 29132461). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 694820). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 18, 2023

Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29132461, 32827181, 31785789) -

Rubinstein-Taybi syndrome due to CREBBP mutations Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Wessex Regional Genetics Laboratory, Salisbury District Hospital

Nov 05, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		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; COSMIC: COSV52116972; COSMIC: COSV52116972;