chr16-3740185-G-T

Variant names:

• chr16-3740185-G-T
• rs11076785
• NM_004380.3:c.4133+214C>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004380.3(CREBBP):​c.4133+214C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.466 in 152,068 control chromosomes in the GnomAD database, including 18,734 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.47 (18734 hom., cov: 33)
• Consequence: CREBBP NM_004380.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.26
• Publications: 15 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.11).
• BP6: Variant 16-3740185-G-T is Benign according to our data. Variant chr16-3740185-G-T is described in ClinVar as Benign. ClinVar VariationId is 1225321.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.716 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CREBBP	NM_004380.3	c.4133+214C>A		intron_variant	Intron 24 of 30	ENST00000262367.10	NP_004371.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CREBBP	ENST00000262367.10	c.4133+214C>A		intron_variant	Intron 24 of 30	1	NM_004380.3	ENSP00000262367.5

Frequencies

GnomAD3 genomes AF: 0.466 AC: 70783 AN: 151950 Hom.: 18689 Cov.: 33

Gnomad AFR AF: 0.722

Gnomad AMI AF: 0.311

Gnomad AMR AF: 0.473

Gnomad ASJ AF: 0.480

Gnomad EAS AF: 0.543

Gnomad SAS AF: 0.486

Gnomad FIN AF: 0.319

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.325

Gnomad OTH AF: 0.456

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.466 AC: 70886 AN: 152068 Hom.: 18734 Cov.: 33 AF XY: 0.465 AC XY: 34571 AN XY: 74338

African (AFR) AF: 0.723 AC: 29968 AN: 41464

American (AMR) AF: 0.473 AC: 7234 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.480 AC: 1663 AN: 3466

East Asian (EAS) AF: 0.544 AC: 2808 AN: 5166

South Asian (SAS) AF: 0.487 AC: 2353 AN: 4828

European-Finnish (FIN) AF: 0.319 AC: 3366 AN: 10568

Middle Eastern (MID) AF: 0.480 AC: 141 AN: 294

European-Non Finnish (NFE) AF: 0.325 AC: 22118 AN: 67978

Other (OTH) AF: 0.451 AC: 951 AN: 2110

Alfa AF: 0.367 Hom.: 17395

Bravo AF: 0.485

Asia WGS AF: 0.529 AC: 1842 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.29
DANN	Benign	0.14
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs11076785; hg19: chr16-3790186;