rs143247685

chr16-3770722-T-Achr16-3770722-T-Cchr16-3770722-T-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004380.3(CREBBP):c.2728A>T(p.Thr910Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,613,886 control chromosomes in the GnomAD database, including 3 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. T910A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00012 (3 hom.)
• Consequence: CREBBP NM_004380.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 1.43

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

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CREBBP
• BP4: Computational evidence support a benign effect (MetaRNN=0.0071692467).
• BP6: Variant 16-3770722-T-A is Benign according to our data. Variant chr16-3770722-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 133924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000592 (9/152042) while in subpopulation SAS AF= 0.00125 (6/4812). AF 95% confidence interval is 0.000543. There are 0 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CREBBP	NM_004380.3	c.2728A>T	p.Thr910Ser	missense_variant	14/31	ENST00000262367.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CREBBP	ENST00000262367.10	c.2728A>T	p.Thr910Ser	missense_variant	14/31	1	NM_004380.3	P1
CREBBP	ENST00000382070.7	c.2614A>T	p.Thr872Ser	missense_variant	13/30	1
CREBBP	ENST00000570939.2	c.1333A>T	p.Thr445Ser	missense_variant	9/23	5
CREBBP	ENST00000573672.1			upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 151926 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000219 AC: 55 AN: 251324 Hom.: 0 AF XY: 0.000302 AC XY: 41 AN XY: 135840

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00173

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000120 AC: 176 AN: 1461844 Hom.: 3 Cov.: 33 AF XY: 0.000160 AC XY: 116 AN XY: 727218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00148

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152042 Hom.: 0 Cov.: 31 AF XY: 0.0000807 AC XY: 6 AN XY: 74324

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000388

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00000454 Hom.: 3

Bravo AF: 0.0000491

ExAC AF: 0.000296 AC: 36

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	CREBBP: PP2, BP4, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 09, 2021	This variant is associated with the following publications: (PMID: 24728327) -

not specified Benign:1 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 16, 2014	- -

CREBBP-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 16, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 2017

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Rubinstein-Taybi syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 08, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	9.7
Dann	Benign	0.77
DEOGEN2	Benign	0.32	T;.;.
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.60
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.49	T;T;T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.0072	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.060	N;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.13	N;N;.
REVEL	Benign	0.12
Sift	Benign	0.71	T;T;.
Sift4G	Benign	0.78	T;T;.
Polyphen		0.0	B;.;.
Vest4		0.11
MutPred		0.17		Loss of glycosylation at T910 (P = 0.0818);.;.;
MVP		0.46
MPC		0.080
ClinPred		0.0045	T
GERP RS		2.2
Varity_R		0.016
gMVP		0.056

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: rs143247685; hg19: chr16-3820723;