rs587783483
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_004380.3(CREBBP):c.3779+1G>T variant causes a splice donor 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
NM_004380.3 splice_donor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
?
Splicing variant, 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;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
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 | UniProt |
---|---|---|---|---|---|---|---|
CREBBP | NM_004380.3 | c.3779+1G>T | splice_donor_variant | ENST00000262367.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CREBBP | ENST00000262367.10 | c.3779+1G>T | splice_donor_variant | 1 | NM_004380.3 | P1 | |||
CREBBP | ENST00000382070.7 | c.3665+1G>T | splice_donor_variant | 1 | |||||
CREBBP | ENST00000570939.2 | c.2414+1G>T | splice_donor_variant | 5 | |||||
CREBBP | ENST00000573517.6 | c.85+1G>T | splice_donor_variant | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
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 | Invitae | 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. - |
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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at