16-3749631-C-T

Position:

chr16-3749631-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_004380.3(CREBBP):c.3832G>A(p.Glu1278Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1278A) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

CREBBP
NM_004380.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 6.74

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 links:

CREBBP (HGNC:):

CREBBP links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CREBBP. . Gene score misZ 3.8991 (greater than the threshold 3.09). Trascript score misZ 4.7573 (greater than threshold 3.09). GenCC has associacion of gene with Menke-Hennekam syndrome 1, Rubinstein-Taybi syndrome due to CREBBP mutations, Rubinstein-Taybi syndrome.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.971

PP5

Variant 16-3749631-C-T is Pathogenic according to our data. Variant chr16-3749631-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3749631-C-T is described in Lovd as [Pathogenic]. Variant chr16-3749631-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CREBBP	NM_004380.3 linkuse as main transcript	c.3832G>A	p.Glu1278Lys	missense_variant	21/31	ENST00000262367.10	NP_004371.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CREBBP	ENST00000262367.10 linkuse as main transcript	c.3832G>A	p.Glu1278Lys	missense_variant	21/31	1	NM_004380.3	ENSP00000262367.5		Q92793-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Rubinstein-Taybi syndrome due to CREBBP mutations

Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Aug 12, 2022	ACMG classification criteria: PS4 moderated, PM1 moderated, PM2 moderated, PM6 moderated, PP3 supporting -
Likely pathogenic, criteria provided, single submitter	clinical testing	Wessex Regional Genetics Laboratory, Salisbury District Hospital	Nov 05, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 15, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 19, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 14, 2022	Observed in multiple unrelated patients with features consistent with Rubinstein-Taybi syndrome in published literature (Kalkhoven et al., 2003; Schorry et al., 2008; Cross et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20689175, 12566391, 17942008, 25158095, 15706485, 18792986, 32827181) -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 17, 2022

- -

CREBBP-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 24, 2024

The CREBBP c.3832G>A variant is predicted to result in the amino acid substitution p.Glu1278Lys. This variant has been reported in multiple individuals with Rubinstein-Taybi syndrome (Kalkhoven et al 2003. PubMed ID: 12566391; Schorry et al. 2008. PubMed ID: 18792986; de novo, Cross et al. 2020. PubMed ID: 32827181). This variant has not been reported in a large population database, indicating this variant is rare. At PreventionGenetics, we have observed this variant occurred de novo in one individual with autism spectrum disorder. This variant is interpreted as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 09, 2019

- -

Abnormality of the nervous system

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Intellectual disability

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Diagnostic Laboratory, Strasbourg University Hospital

Sep 10, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

D;.;.

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D;D

M_CAP

Pathogenic

0.74

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.3

M;.;.

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-3.6

D;D;.

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0010

D;D;.

Sift4G

Uncertain

0.0030

D;D;.

Polyphen

1.0

D;.;.

Vest4

0.97

MutPred

0.86

Gain of methylation at E1278 (P = 0.0068);.;.;

MVP

0.99

MPC

1.3

ClinPred

1.0

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.85

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over