chr16-3751725-C-A

Variant names:

• chr16-3751725-C-A
• rs587783483
• NM_004380.3:c.3779+1G>T

Variant summary

Our verdict is Pathogenic. The variant received 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
• Publications: 6 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.011051985 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 CliVar as Pathogenic. Clinvar id is 694820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3751725-C-A is described in CliVar as Pathogenic. Clinvar id is 694820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3751725-C-A is described in CliVar as Pathogenic. Clinvar id is 694820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3751725-C-A is described in CliVar as Pathogenic. Clinvar id is 694820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3751725-C-A is described in CliVar as Pathogenic. Clinvar id is 694820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3751725-C-A is described in CliVar 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 rank	MANE	Protein	UniProt
CREBBP	NM_004380.3	c.3779+1G>T		splice_donor_variant, intron_variant	Intron 20 of 30	ENST00000262367.10	NP_004371.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CREBBP	ENST00000262367.10	c.3779+1G>T		splice_donor_variant, intron_variant	Intron 20 of 30	1	NM_004380.3	ENSP00000262367.5
CREBBP	ENST00000382070.7	c.3665+1G>T		splice_donor_variant, intron_variant	Intron 19 of 29	1		ENSP00000371502.3
CREBBP	ENST00000570939.2	c.2414+1G>T		splice_donor_variant, intron_variant	Intron 15 of 22	5		ENSP00000461002.2
CREBBP	ENST00000573517.6	c.83+1G>T		splice_donor_variant, intron_variant	Intron 2 of 6	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

Oct 11, 2022

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 694820). 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. This variant is not present in population databases (gnomAD no frequency). 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). -

not provided Pathogenic:1

Aug 18, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 05, 2019

Wessex Regional Genetics Laboratory, Salisbury District Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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
PhyloP100		7.6
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587783483; hg19: chr16-3801726; COSMIC: COSV52116972; COSMIC: COSV52116972;