16-3761595-C-T

Variant names:

• chr16-3761595-C-T
• rs11076786
• NM_004380.3:c.3251-2623G>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004380.3(CREBBP):​c.3251-2623G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 517,814 control chromosomes in the GnomAD database, including 3,638 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.13 (1577 hom., cov: 31)
  • Exomes 𝑓: 0.098 (2061 hom.)
• Consequence: CREBBP NM_004380.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.06

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.223 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CREBBP	NM_004380.3	c.3251-2623G>A		intron_variant	Intron 16 of 30	ENST00000262367.10	NP_004371.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CREBBP	ENST00000262367.10	c.3251-2623G>A		intron_variant	Intron 16 of 30	1	NM_004380.3	ENSP00000262367.5
CREBBP	ENST00000382070.7	c.3137-2623G>A		intron_variant	Intron 15 of 29	1		ENSP00000371502.3
CREBBP	ENST00000570939.2	c.1856-2623G>A		intron_variant	Intron 11 of 22	5		ENSP00000461002.2

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19847 AN: 151976 Hom.: 1571 Cov.: 31

Gnomad AFR AF: 0.226

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.0811

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.178

Gnomad SAS AF: 0.0790

Gnomad FIN AF: 0.0843

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.0918

Gnomad OTH AF: 0.141

GnomAD3 exomes AF: 0.103 AC: 23486 AN: 227276 Hom.: 1457 AF XY: 0.102 AC XY: 12770 AN XY: 125770

Gnomad AFR exome AF: 0.233

Gnomad AMR exome AF: 0.0527

Gnomad ASJ exome AF: 0.135

Gnomad EAS exome AF: 0.178

Gnomad SAS exome AF: 0.0766

Gnomad FIN exome AF: 0.0844

Gnomad NFE exome AF: 0.0974

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.0977 AC: 35749 AN: 365720 Hom.: 2061 Cov.: 0 AF XY: 0.0964 AC XY: 20225 AN XY: 209756

Gnomad4 AFR exome AF: 0.228

Gnomad4 AMR exome AF: 0.0530

Gnomad4 ASJ exome AF: 0.138

Gnomad4 EAS exome AF: 0.184

Gnomad4 SAS exome AF: 0.0792

Gnomad4 FIN exome AF: 0.0819

Gnomad4 NFE exome AF: 0.0969

Gnomad4 OTH exome AF: 0.110

GnomAD4 genome AF: 0.131 AC: 19881 AN: 152094 Hom.: 1577 Cov.: 31 AF XY: 0.129 AC XY: 9585 AN XY: 74338

Gnomad4 AFR AF: 0.226

Gnomad4 AMR AF: 0.0810

Gnomad4 ASJ AF: 0.123

Gnomad4 EAS AF: 0.177

Gnomad4 SAS AF: 0.0795

Gnomad4 FIN AF: 0.0843

Gnomad4 NFE AF: 0.0918

Gnomad4 OTH AF: 0.144

Alfa AF: 0.101 Hom.: 1251

Bravo AF: 0.138

Asia WGS AF: 0.120 AC: 417 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.16
DANN	Benign	0.49

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: rs11076786; hg19: chr16-3811596;