rs587783497

Positions:

• chr16-3736702-T-A
• chr16-3736702-T-C
• chr16-3736702-T-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS1_Moderate PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_004380.3(CREBBP):​c.4508A>T​(p.Tyr1503Phe) variant causes a missense 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. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y1503H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CREBBP NM_004380.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 8.02

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 13 ACMG points.

• PS1: Transcript NM_004380.3 (CREBBP) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-3736703-A-G is described in Lovd as [Pathogenic].
• 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, 0.98
• PP5: Variant 16-3736702-T-A is Pathogenic according to our data. Variant chr16-3736702-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3258003.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CREBBP	NM_004380.3	c.4508A>T	p.Tyr1503Phe	missense_variant	27/31	ENST00000262367.10	NP_004371.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CREBBP	ENST00000262367.10	c.4508A>T	p.Tyr1503Phe	missense_variant	27/31	1	NM_004380.3	ENSP00000262367	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rubinstein-Taybi syndrome due to CREBBP mutations Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

May 20, 2023

The observed missense c.4508A>T(p.Tyr1503Phe) variant in CREBBP gene has been reported previously in heterozygous state in individual(s) affected with Rubinstein–Taybi syndrome (Spena et al., 2015). This variant is absent in gnomAD Exomes. The same position with different substituational variant c.4508A>G (p.Tyr1503Cys) has been reported in ClinVar as Pathogenic. The amino acid Tyr at position 1503 is changed to a Phe changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Tyr1503Phe in CREBBP is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Multiple lines of computational evidence (Polyphen - Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. This Tyr1503Phe mutation is involving in both HAT (histone acetyltrasferase) and CoABS (coenzyme A binding site) functional domains (Spena et al., 2015). Same amino acid change as a previously established pathogenic variant regardless of nucleotide change has been observed. For these reasons, this variant has been classified as Likely Pathogenic. -

Neoplasm Other:1

-, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.98	D;.;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.9	D;D;.
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0030	D;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.82
MutPred		0.90		Gain of methylation at K1504 (P = 0.0267);.;.;
MVP		0.94
MPC		1.0
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.55
gMVP		0.94

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-3786703; COSMIC: COSV52117486; COSMIC: COSV52117486;