rs199990883

Variant names:

• chr16-3729328-C-T
• rs199990883
• NM_004380.3:c.5719G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-3729328-C-T
• chr16-3729328-C-A
• chr16-3729328-C-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004380.3(CREBBP):​c.5719G>A​(p.Ala1907Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0017 in 1,572,556 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (6 hom.)
• Consequence: CREBBP NM_004380.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: 0.353
• Publications: 6 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: Illumina, ClinGen
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009790987).
• BP6: Variant 16-3729328-C-T is Benign according to our data. Variant chr16-3729328-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 95056.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00122 (185/151664) while in subpopulation SAS AF = 0.00188 (9/4794). AF 95% confidence interval is 0.00157. There are 0 homozygotes in GnomAd4. There are 84 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 185 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004380.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CREBBP	NM_004380.3	MANE Select	c.5719G>A	p.Ala1907Thr	missense	Exon 31 of 31	NP_004371.2	Q92793-1
	CREBBP	NM_001079846.1		c.5605G>A	p.Ala1869Thr	missense	Exon 30 of 30	NP_001073315.1	Q92793-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CREBBP	ENST00000262367.10	TSL:1 MANE Select	c.5719G>A	p.Ala1907Thr	missense	Exon 31 of 31	ENSP00000262367.5	Q92793-1
	CREBBP	ENST00000382070.7	TSL:1	c.5605G>A	p.Ala1869Thr	missense	Exon 30 of 30	ENSP00000371502.3	Q92793-2

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 185 AN: 151546 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000510

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00188

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00183

Gnomad OTH AF: 0.00289

GnomAD2 exomes AF: 0.00154 AC: 288 AN: 186422 AF XY: 0.00172

Gnomad AFR exome AF: 0.000350

Gnomad AMR exome AF: 0.000935

Gnomad ASJ exome AF: 0.000781

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00187

Gnomad OTH exome AF: 0.00338

GnomAD4 exome AF: 0.00175 AC: 2490 AN: 1420892 Hom.: 6 Cov.: 35 AF XY: 0.00183 AC XY: 1287 AN XY: 704458

African (AFR) AF: 0.000641 AC: 21 AN: 32786

American (AMR) AF: 0.00114 AC: 44 AN: 38640

Ashkenazi Jewish (ASJ) AF: 0.000862 AC: 22 AN: 25522

East Asian (EAS) AF: 0.00 AC: 0 AN: 37846

South Asian (SAS) AF: 0.00293 AC: 244 AN: 83182

European-Finnish (FIN) AF: 0.000218 AC: 9 AN: 41338

Middle Eastern (MID) AF: 0.00954 AC: 53 AN: 5554

European-Non Finnish (NFE) AF: 0.00179 AC: 1964 AN: 1096868

Other (OTH) AF: 0.00225 AC: 133 AN: 59156

GnomAD4 genome AF: 0.00122 AC: 185 AN: 151664 Hom.: 0 Cov.: 32 AF XY: 0.00113 AC XY: 84 AN XY: 74090

African (AFR) AF: 0.000508 AC: 21 AN: 41334

American (AMR) AF: 0.00125 AC: 19 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.00188 AC: 9 AN: 4794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10536

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00183 AC: 124 AN: 67854

Other (OTH) AF: 0.00286 AC: 6 AN: 2098

Alfa AF: 0.00146 Hom.: 0

Bravo AF: 0.00131

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00188 AC: 16

ExAC AF: 0.00142 AC: 171

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	3	not specified (3)
-	-	1	CREBBP-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Rubinstein-Taybi syndrome (1)
-	1	-	Rubinstein-Taybi syndrome due to CREBBP mutations (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	7.7
DANN	Benign	0.75
DEOGEN2	Benign	0.39	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0098	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.46	N
PhyloP100		0.35
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.63	N
REVEL	Uncertain	0.50
Sift	Benign	0.51	T
Sift4G	Benign	0.61	T
Polyphen		0.0	B
Vest4		0.088
MVP		0.97
MPC		1.3
ClinPred		0.00087	T
GERP RS		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.033
gMVP		0.041
Mutation Taster		=95/5	polymorphism

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: rs199990883; hg19: chr16-3779329; COSMIC: COSV52118799; COSMIC: COSV52118799;