16-3740543-T-C

Position:

• chr16-3740543-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_004380.3(CREBBP):​c.3989A>G​(p.Gln1330Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CREBBP NM_004380.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.01

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CREBBP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CREBBP	NM_004380.3	c.3989A>G	p.Gln1330Arg	missense_variant	24/31	ENST00000262367.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CREBBP	ENST00000262367.10	c.3989A>G	p.Gln1330Arg	missense_variant	24/31	1	NM_004380.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rubinstein-Taybi syndrome due to CREBBP mutations Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 03, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D;.;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.050	D
MetaRNN	Uncertain	0.56	D;D;D
MetaSVM	Uncertain	0.039	D
MutationAssessor	Benign	1.5	L;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-2.2	N;N;.
REVEL	Uncertain	0.58
Sift	Uncertain	0.015	D;D;.
Sift4G	Uncertain	0.0060	D;D;.
Polyphen		0.96	D;.;.
Vest4		0.68
MutPred		0.51		Gain of catalytic residue at Q1330 (P = 0.0211);.;.;
MVP		0.73
MPC		1.2
ClinPred		0.79	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.78

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: rs587783487; hg19: chr16-3790544;