16-3731314-A-G

Variant names:

• chr16-3731314-A-G
• rs587783503
• NM_004380.3:c.5050T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_004380.3(CREBBP):​c.5050T>C​(p.Ser1684Pro) 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. S1684Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CREBBP NM_004380.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.29
• Publications: 1 publications found

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]

CREBBP Gene-Disease associations (from GenCC):

• Rubinstein-Taybi syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Illumina
• Rubinstein-Taybi syndrome due to CREBBP mutations

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• Menke-Hennekam syndrome 1

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 2 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.842
• PP5: Variant 16-3731314-A-G is Pathogenic according to our data. Variant chr16-3731314-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 158385.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-3731314-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 158385.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-3731314-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 158385.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-3731314-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 158385.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CREBBP	NM_004380.3	c.5050T>C	p.Ser1684Pro	missense_variant	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.5050T>C	p.Ser1684Pro	missense_variant	Exon 30 of 31	1	NM_004380.3	ENSP00000262367.5
CREBBP	ENST00000382070.7	c.4936T>C	p.Ser1646Pro	missense_variant	Exon 29 of 30	1		ENSP00000371502.3
CREBBP	ENST00000637492.1	c.-66T>C		upstream_gene_variant		5		ENSP00000490244.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000573 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rubinstein-Taybi syndrome due to CREBBP mutations Pathogenic:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.046	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	0.058	D
MutationAssessor	Benign	1.1	L;.
PhyloP100		7.3
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.1	D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		0.99	D;.
Vest4		0.83
MutPred		0.53		Gain of glycosylation at S1684 (P = 0.0237);.;
MVP		0.97
MPC		1.7
ClinPred		0.94	D
GERP RS		5.9
PromoterAI		0.012	Neutral
Varity_R		0.85
gMVP		0.90
Mutation Taster		=70/30	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587783503; hg19: chr16-3781315;