16-3757288-C-T

Variant names:

• chr16-3757288-C-T
• rs1057518844
• NM_004380.3:c.3698G>A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_004380.3(CREBBP):​c.3698G>A​(p.Arg1233Lys) variant causes a missense, splice region 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. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CREBBP NM_004380.3 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.91

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 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the CREBBP gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 106 curated pathogenic missense variants (we use a threshold of 10). The gene has 165 curated benign missense variants. Gene score misZ: 3.8991 (above the threshold of 3.09). Trascript score misZ: 4.7573 (above the threshold of 3.09). GenCC associations: The gene is linked to Menke-Hennekam syndrome 1, Rubinstein-Taybi syndrome due to CREBBP mutations, Rubinstein-Taybi syndrome.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 16-3757288-C-T is Pathogenic according to our data. Variant chr16-3757288-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 374025.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.3698G>A	p.Arg1233Lys	missense_variant, splice_region_variant	Exon 19 of 31	ENST00000262367.10	NP_004371.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CREBBP	ENST00000262367.10	c.3698G>A	p.Arg1233Lys	missense_variant, splice_region_variant	Exon 19 of 31	1	NM_004380.3	ENSP00000262367.5
CREBBP	ENST00000382070.7	c.3584G>A	p.Arg1195Lys	missense_variant, splice_region_variant	Exon 18 of 30	1		ENSP00000371502.3
CREBBP	ENST00000570939.2	c.2303G>A	p.Ser768Asn	missense_variant, splice_region_variant	Exon 14 of 23	5		ENSP00000461002.2
CREBBP	ENST00000573517.6	c.2G>A	p.Arg1Lys	missense_variant, splice_region_variant	Exon 1 of 7	5		ENSP00000460474.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rubinstein-Taybi syndrome Pathogenic:1

May 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 1233 of the CREBBP protein (p.Arg1233Lys). This variant also falls at the last nucleotide of exon 19, which is part of the consensus splice site for this exon. 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 (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 374025). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). For these reasons, this variant has been classified as Pathogenic. -

Glaucoma;C0575897:Thumb deformity Pathogenic:1

Dec 03, 2015

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rubinstein-Taybi syndrome due to CREBBP mutations Pathogenic:1

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Likely pathogenic. This variant arose de novo in at least one reported proband. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	32
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.85	D;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.062	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-2.8	D;D
REVEL	Pathogenic	0.68
Sift	Benign	0.10	T;T
Sift4G	Uncertain	0.0060	D;D
Polyphen		0.96	P;.
Vest4		0.78
MutPred		0.49		Gain of methylation at R1233 (P = 0.0042);.;
MVP		0.90
MPC		1.1
ClinPred		0.95	D
GERP RS		6.0
Varity_R		0.66
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.010		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: rs1057518844; hg19: chr16-3807289;