16-3751725-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_004380.3(CREBBP):c.3779+1G>A 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)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CREBBP
NM_004380.3 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 7.57

Publications

6 publications found

Variant links:

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)

CREBBP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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-T is Pathogenic according to our data. Variant chr16-3751725-C-T is described in CliVar as Pathogenic. Clinvar id is 158359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3751725-C-T is described in CliVar as Pathogenic. Clinvar id is 158359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3751725-C-T is described in CliVar as Pathogenic. Clinvar id is 158359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3751725-C-T is described in CliVar as Pathogenic. Clinvar id is 158359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3751725-C-T is described in CliVar as Pathogenic. Clinvar id is 158359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3751725-C-T is described in CliVar as Pathogenic. Clinvar id is 158359.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 link	c.3779+1G>A		splice_donor_variant, intron_variant	Intron 20 of 30	ENST00000262367.10	NP_004371.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CREBBP	ENST00000262367.10 link	c.3779+1G>A	splice_donor_variant, intron_variant	Intron 20 of 30	1	NM_004380.3	ENSP00000262367.5	Q92793-1
CREBBP	ENST00000382070.7 link	c.3665+1G>A	splice_donor_variant, intron_variant	Intron 19 of 29	1		ENSP00000371502.3	Q92793-2
CREBBP	ENST00000570939.2 link	c.2414+1G>A	splice_donor_variant, intron_variant	Intron 15 of 22	5		ENSP00000461002.2	I3L466
CREBBP	ENST00000573517.6 link	c.83+1G>A	splice_donor_variant, intron_variant	Intron 2 of 6	5		ENSP00000460474.2	I3L3I5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461682

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727162

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111830

Other (OTH)

AF:

0.00

AC:

AN:

60386

GnomAD4 genome

Cov.:

Alfa

AF:

0.00000535

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Rubinstein-Taybi syndrome due to CREBBP mutations

Pathogenic:6

Nov 29, 2022

Laboratory of Medical Genetics, University of Torino

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Feb 26, 2013

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 27, 2022

Daryl Scott Lab, Baylor College of Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 25, 2024

Institute of Immunology and Genetics Kaiserslautern

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG Criteria: PM2, PP3, PVS1, PP5; Variant was found in heterozygous state -

Dec 09, 2014

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Nov 05, 2019

Wessex Regional Genetics Laboratory, Salisbury District Hospital

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Rubinstein-Taybi syndrome due to CREBBP mutations;C5193034:Menke-Hennekam syndrome 1

Pathogenic:1

Feb 07, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Rubinstein-Taybi syndrome

Pathogenic:1

Apr 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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, 32827181). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 158359). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Apr 26, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27165009, 31515782, 32827181) -

Intellectual disability

Pathogenic:1

Sep 10, 2020

Diagnostic Laboratory, Strasbourg University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

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)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

Splicevardb

3.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over