rs886039331

Variant names:

• chr16-3729037-G-A
• rs886039331
• NM_004380.3:c.6010C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-3729037-G-A
• chr16-3729037-G-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_004380.3(CREBBP):​c.6010C>T​(p.Arg2004*) variant causes a stop gained change. 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 Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CREBBP NM_004380.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.72

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

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 34 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-3729037-G-A is Pathogenic according to our data. Variant chr16-3729037-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 265084.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-3729037-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CREBBP	NM_004380.3	c.6010C>T	p.Arg2004*	stop_gained	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.6010C>T	p.Arg2004*	stop_gained	Exon 31 of 31	1	NM_004380.3	ENSP00000262367.5
CREBBP	ENST00000382070.7	c.5896C>T	p.Arg1966*	stop_gained	Exon 30 of 30	1		ENSP00000371502.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1436878 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 714344

African (AFR) AF: 0.00 AC: 0 AN: 33156

American (AMR) AF: 0.00 AC: 0 AN: 42634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25770

East Asian (EAS) AF: 0.00 AC: 0 AN: 38808

South Asian (SAS) AF: 0.00 AC: 0 AN: 84470

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105374

Other (OTH) AF: 0.00 AC: 0 AN: 59628

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Mar 15, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation, as the last 439 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15706485, 21932317) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.93	D
PhyloP100		4.7
Vest4		0.91
GERP RS		5.1
Mutation Taster		=4/196	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

Publications

LitVar

Other links and lift over

dbSNP: rs886039331; hg19: chr16-3779038; COSMIC: COSV52145056;