16-3729447-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_004380.3(CREBBP):c.5600G>A(p.Arg1867Gln) 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R1867W) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CREBBP NM_004380.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1
• Conservation: PhyloP100: 7.78

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 17 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_004380.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-3729448-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 871516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, CREBBP
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.841
• PP5: Variant 16-3729447-C-T is Pathogenic according to our data. Variant chr16-3729447-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 429336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3729447-C-T is described in Lovd as [Likely_pathogenic]. Variant chr16-3729447-C-T is described in Lovd as [Pathogenic]. Variant chr16-3729447-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CREBBP	NM_004380.3	c.5600G>A	p.Arg1867Gln	missense_variant	31/31	ENST00000262367.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CREBBP	ENST00000262367.10	c.5600G>A	p.Arg1867Gln	missense_variant	31/31	1	NM_004380.3	P1
CREBBP	ENST00000382070.7	c.5486G>A	p.Arg1829Gln	missense_variant	30/30	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Menke-Hennekam syndrome 1 Pathogenic:1 Uncertain:1

Uncertain significance, no assertion criteria provided	clinical testing	Al Jawhara Center for Molecular Medicine, Arabian Gulf University	Jan 20, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 22, 2019	- -

Rubinstein-Taybi syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1867 of the CREBBP protein (p.Arg1867Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of CREBBP-related conditions (PMID: 27311832, 29460469). ClinVar contains an entry for this variant (Variation ID: 429336). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CREBBP protein function. This variant disrupts the p.Arg1867 amino acid residue in CREBBP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27311832). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 18, 2020

Not observed 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: 27311832, 29460469) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.9	D;D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.013	D;D
Sift4G	Uncertain	0.019	D;D
Polyphen		1.0	D;.
Vest4		0.91
MutPred		0.35		Loss of methylation at R1868 (P = 0.1612);.;
MVP		0.95
MPC		1.5
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.49
gMVP		0.75

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: rs1131691326; hg19: chr16-3779448;