16-3770722-T-C

Variant names:

• chr16-3770722-T-C
• rs143247685
• NM_004380.3:c.2728A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004380.3(CREBBP):​c.2728A>G​(p.Thr910Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00238 in 1,613,886 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T910S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0024 (9 hom.)
• Consequence: CREBBP NM_004380.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:2 B:14
• Conservation: PhyloP100: 1.43
• Publications: 14 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005923271).
• BP6: Variant 16-3770722-T-C is Benign according to our data. Variant chr16-3770722-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 30042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00232 (353/152042) while in subpopulation NFE AF = 0.00315 (214/67968). AF 95% confidence interval is 0.0028. There are 0 homozygotes in GnomAd4. There are 199 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 353 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.2728A>G	p.Thr910Ala	missense	Exon 14 of 31	NP_004371.2
	CREBBP	NM_001079846.1		c.2614A>G	p.Thr872Ala	missense	Exon 13 of 30	NP_001073315.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CREBBP	ENST00000262367.10	TSL:1 MANE Select	c.2728A>G	p.Thr910Ala	missense	Exon 14 of 31	ENSP00000262367.5
	CREBBP	ENST00000382070.7	TSL:1	c.2614A>G	p.Thr872Ala	missense	Exon 13 of 30	ENSP00000371502.3
	CREBBP	ENST00000570939.2	TSL:5	c.1333A>G	p.Thr445Ala	missense	Exon 9 of 23	ENSP00000461002.2

Frequencies

GnomAD3 genomes AF: 0.00232 AC: 353 AN: 151926 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0109

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00315

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00240 AC: 603 AN: 251324 AF XY: 0.00226

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00953

Gnomad NFE exome AF: 0.00311

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00239 AC: 3487 AN: 1461844 Hom.: 9 Cov.: 33 AF XY: 0.00239 AC XY: 1739 AN XY: 727218

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00161 AC: 42 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86256

European-Finnish (FIN) AF: 0.00923 AC: 493 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00249 AC: 2771 AN: 1111994

Other (OTH) AF: 0.00267 AC: 161 AN: 60394

GnomAD4 genome AF: 0.00232 AC: 353 AN: 152042 Hom.: 0 Cov.: 31 AF XY: 0.00268 AC XY: 199 AN XY: 74324

African (AFR) AF: 0.000362 AC: 15 AN: 41474

American (AMR) AF: 0.0000655 AC: 1 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.0109 AC: 115 AN: 10572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00315 AC: 214 AN: 67968

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00211 Hom.: 4

Bravo AF: 0.00144

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.00233 AC: 283

EpiCase AF: 0.00234

EpiControl AF: 0.00213

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	4	not specified (4)
-	-	1	CREBBP-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Intellectual disability (1)
-	-	1	Rubinstein-Taybi syndrome (1)
1	-	-	Rubinstein-Taybi syndrome due to CREBBP mutations (1)
1	-	-	Tip-toe gait (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	13
DANN	Benign	0.82
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.61
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.0	L
PhyloP100		1.4
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.14
Sift	Benign	0.71	T
Sift4G	Benign	0.77	T
Polyphen		0.0	B
Vest4		0.086
MVP		0.59
MPC		0.087
ClinPred		0.00086	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.018
gMVP		0.081
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs143247685; hg19: chr16-3820723; COSMIC: COSV52120594;