16-3751725-C-G

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_004380.3(CREBBP):​c.3779+1G>C 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CREBBP NM_004380.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• 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: Likely_pathogenic. The variant received 6 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-G is Pathogenic according to our data. Variant chr16-3751725-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 975524.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-3751725-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 975524.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-3751725-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 975524.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-3751725-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 975524.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-3751725-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 975524.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-3751725-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 975524.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

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

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Rubinstein-Taybi syndrome due to CREBBP mutations Pathogenic:2

Jun 12, 2020

New York Genome Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3779+1G>C canonical splice site variant identified in the CREBBP gene has not been reported in the literature. A de novo allelic variant c.3779+1G>A has been reported in anindividual with intellectual disability, short stature, dysmorphic features, but no broad thumbs or great toes as usually seen in Rubinstein-Taybi syndrome [PMID: 27165009] and another de novo allelic variant c.3779+1G>T has been reported in an individual with classical Rubinstein-Taybi syndrome phenotype [PMID: 29132461]. The c.3779+1G>C splice site variant is not reported in gnomAD database indicating this is a rare allele and predicted to damage the canonical splice donor site in intron 20, leads to skipping of exon 20 resulting in-frame deletion of 81 bp in the CREBBP gene [PMID: 27165009]. At the protein level, the deletion of 27 amino acids partially deletes the DUF902 domain which is localized in the histone acetyltransferase (HAT) domain. As most missense mutations found in Rubinstein-Taybi syndrome are clustered in the HAT domain, it was suggested that loss of HAT activity may be sufficient to cause Rubinstein-Taybi syndrome [PMID: 27165009]. Based on the available evidence, the variant c.3779+1G>C in the CREBBP gene is classified as likely pathogenic. -

Jan 01, 2019

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

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	0.33
CADD	Pathogenic	35
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
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)		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

Other links and lift over

dbSNP: rs587783483; hg19: chr16-3801726;