rs1555471323

Variant names:

• chr16-3729343-TCTGGGGTGTG-T
• rs1555471323
• NM_004380.3:c.5694_5703delCACACCCCAG

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_004380.3(CREBBP):​c.5694_5703delCACACCCCAG​(p.Ser1898ArgfsTer14) variant causes a frameshift 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CREBBP NM_004380.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.91

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-3729343-TCTGGGGTGTG-T is Pathogenic according to our data. Variant chr16-3729343-TCTGGGGTGTG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 458203.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.5694_5703delCACACCCCAG	p.Ser1898ArgfsTer14	frameshift_variant	Exon 31 of 31	ENST00000262367.10	NP_004371.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CREBBP	ENST00000262367.10	c.5694_5703delCACACCCCAG	p.Ser1898ArgfsTer14	frameshift_variant	Exon 31 of 31	1	NM_004380.3	ENSP00000262367.5
CREBBP	ENST00000382070.7	c.5580_5589delCACACCCCAG	p.Ser1860ArgfsTer14	frameshift_variant	Exon 30 of 30	1		ENSP00000371502.3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rubinstein-Taybi syndrome Pathogenic:1

May 17, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Two different truncations downstream of this variant (p.Ser2015Alafs*25 and  p.Gln2022Argfs*16) have been determined to be pathogenic (PMID: 17052327). This suggests that deletion of this region of the CREBBP protein is causative of disease. This sequence change results in a premature translational stop signal in the CREBBP (p.Ser1898Argfs*14). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 545 amino acids of the CREBBP protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a CREBBP-related disease. For these reasons, this variant has been classified as Pathogenic. -

Rubinstein-Taybi syndrome due to CREBBP mutations Pathogenic:1

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed frameshift c.5694_5703del (p.Ser1898ArgfsTer14) variant in CREBBP gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Ala420ProfsTer11 variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic. This variant causes a frameshift starting with codon Serine 1898, changes this amino acid to Arginine residue, and creates a premature Stop codon at position 14 of the new reading frame, denoted p.Ser1898ArgfsTer14. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants of CREBBP gene have been previously reported to be disease causing (Bentivegna et al., 2006). However, additional functional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555471323; hg19: chr16-3779344;