16-3745291-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004380.3(CREBBP):c.3900C>A(p.Ile1300=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0164 in 1,613,834 control chromosomes in the GnomAD database, including 1,500 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (172 hom., cov: 33)
  • Exomes 𝑓: 0.016 (1328 hom.)
• Consequence: CREBBP NM_004380.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.97

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 16-3745291-G-T is Benign according to our data. Variant chr16-3745291-G-T is described in ClinVar as [Benign]. Clinvar id is 158362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.97 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CREBBP	NM_004380.3	c.3900C>A	p.Ile1300=	synonymous_variant	22/31	ENST00000262367.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CREBBP	ENST00000262367.10	c.3900C>A	p.Ile1300=	synonymous_variant	22/31	1	NM_004380.3	P1

Frequencies

GnomAD3 genomes AF: 0.0250 AC: 3801 AN: 152200 Hom.: 171 Cov.: 33

Gnomad AFR AF: 0.0383

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0170

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00344

Gnomad OTH AF: 0.0229

GnomAD3 exomes AF: 0.0349 AC: 8744 AN: 250754 Hom.: 592 AF XY: 0.0377 AC XY: 5108 AN XY: 135554

Gnomad AFR exome AF: 0.0383

Gnomad AMR exome AF: 0.00993

Gnomad ASJ exome AF: 0.0103

Gnomad EAS exome AF: 0.201

Gnomad SAS exome AF: 0.111

Gnomad FIN exome AF: 0.00171

Gnomad NFE exome AF: 0.00374

Gnomad OTH exome AF: 0.0215

GnomAD4 exome AF: 0.0155 AC: 22723 AN: 1461516 Hom.: 1328 Cov.: 31 AF XY: 0.0183 AC XY: 13275 AN XY: 727024

Gnomad4 AFR exome AF: 0.0423

Gnomad4 AMR exome AF: 0.0103

Gnomad4 ASJ exome AF: 0.0117

Gnomad4 EAS exome AF: 0.170

Gnomad4 SAS exome AF: 0.109

Gnomad4 FIN exome AF: 0.00223

Gnomad4 NFE exome AF: 0.00233

Gnomad4 OTH exome AF: 0.0253

GnomAD4 genome AF: 0.0250 AC: 3803 AN: 152318 Hom.: 172 Cov.: 33 AF XY: 0.0274 AC XY: 2041 AN XY: 74480

Gnomad4 AFR AF: 0.0383

Gnomad4 AMR AF: 0.0170

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.192

Gnomad4 SAS AF: 0.116

Gnomad4 FIN AF: 0.00207

Gnomad4 NFE AF: 0.00344

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.00981 Hom.: 16

Bravo AF: 0.0263

Asia WGS AF: 0.137 AC: 475 AN: 3478

EpiCase AF: 0.00469

EpiControl AF: 0.00457

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 2016

This alteration is classified as 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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
Cadd	Benign	14
Dann	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs129974; hg19: chr16-3795292; COSMIC: COSV52117708; COSMIC: COSV52117708;