rs587783502

Variant names:

• chr16-3731322-AAGG-A
• rs587783502
• NM_004380.3:c.5039_5041delCCT

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4_Supporting PP5

The NM_004380.3(CREBBP):​c.5039_5041delCCT​(p.Ser1680del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CREBBP NM_004380.3 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 U:1 O:1
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_004380.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 16-3731322-AAGG-A is Pathogenic according to our data. Variant chr16-3731322-AAGG-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158384.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, other=1, Uncertain_significance=1, Pathogenic=6}. Variant chr16-3731322-AAGG-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CREBBP	NM_004380.3	c.5039_5041delCCT	p.Ser1680del	disruptive_inframe_deletion	Exon 30 of 31	ENST00000262367.10	NP_004371.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CREBBP	ENST00000262367.10	c.5039_5041delCCT	p.Ser1680del	disruptive_inframe_deletion	Exon 30 of 31	1	NM_004380.3	ENSP00000262367.5
CREBBP	ENST00000382070.7	c.4925_4927delCCT	p.Ser1642del	disruptive_inframe_deletion	Exon 29 of 30	1		ENSP00000371502.3
CREBBP	ENST00000637492.1	c.-77_-75delCCT		upstream_gene_variant		5		ENSP00000490244.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461804 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 727194

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rubinstein-Taybi syndrome due to CREBBP mutations Pathogenic:4 Uncertain:1

Jul 09, 2021

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Oct 17, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 05, 2019

Wessex Regional Genetics Laboratory, Salisbury District Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Menke-Hennekam syndrome 1 (MIM#618332) and Rubinstein-Taybi syndrome 1 (MIM#180849). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0213 - In-frame deletion in a non-repetitive region that has high conservation. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in at least five individuals or fetuses with Rubinstein-Taybi syndrome 1 (RTS), suspected RTS or congenital anomalies and dysmorphic facial features, with the variant shown to be de novo in three individuals or fetuses (PMIDs: 18792986, 30633342, 32827181). In addition this variant has been demonstrated to be de novo, and mosaic in one individual with a diffential diagnosis of RTS and Filippi syndrome (MIM#272440) (PMID: 26956253). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

CREBBP-related disorder Pathogenic:1

Apr 04, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CREBBP c.5039_5041delCCT variant is predicted to result in an in-frame deletion (p.Ser1680del). This variant has been reported in individuals with Rubinstein-Taybi syndrome (ID 140, BG, Schorry et al. 2008. PubMed ID: 18792986; Cross et al. 2020. PubMed ID: 32827181) and was also identified in fetal cases of Rubinstein-Taybi syndrome (Cases 5 and 9, Van-Gils et al. 2019. PubMed ID: 30633342). This variant was also seen as a low-level mosaic variant in DNA isolated from buccal mucosa, but was not present in blood, in an individual with clinical features of Rubinstein-Taybi and Filippi syndromes (de Vries et al. 2016. PubMed ID: 26956253). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Rubinstein-Taybi syndrome Pathogenic:1

Mar 19, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.5039_5041del, results in the deletion of 1 amino acid(s) of the CREBBP protein (p.Ser1680del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with CREBBP-related conditions (PMID: 18792986, 30633342, 32827181). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 158384). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Mar 05, 2021

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS2, PS4, PM2, PM4 -

Neoplasm Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: -

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs587783502; hg19: chr16-3781323;