16-3729686-G-T

Variant names:

• chr16-3729686-G-T
• rs375462934
• NM_004380.3:c.5361C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP5_Moderate

The NM_004380.3(CREBBP):​c.5361C>A​(p.Asn1787Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1787I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CREBBP NM_004380.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.257
• Publications: 2 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 6 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_004380.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-3729686-G-T is Pathogenic according to our data. Variant chr16-3729686-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 521033.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.5361C>A	p.Asn1787Lys	missense_variant	Exon 31 of 31	ENST00000262367.10	NP_004371.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CREBBP	ENST00000262367.10	c.5361C>A	p.Asn1787Lys	missense_variant	Exon 31 of 31	1	NM_004380.3	ENSP00000262367.5
CREBBP	ENST00000382070.7	c.5247C>A	p.Asn1749Lys	missense_variant	Exon 30 of 30	1		ENSP00000371502.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Jul 15, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	17
DANN	Benign	0.91
DEOGEN2	Pathogenic	0.87	D;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.31	N
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.2	L;.
PhyloP100		-0.26
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.0	D;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.0050	D;D
Vest4		0.76
ClinPred		0.96	D
GERP RS		-5.8
Varity_R		0.68
gMVP		0.89
Mutation Taster		=12/88	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: rs375462934; hg19: chr16-3779687;