chr16-3727696-A-G

Position:

• chr16-3727696-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004380.3(CREBBP):​c.*22T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0182 in 1,613,564 control chromosomes in the GnomAD database, including 4,061 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.092 (2151 hom., cov: 31)
  • Exomes 𝑓: 0.010 (1910 hom.)
• Consequence: CREBBP NM_004380.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0430

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 16-3727696-A-G is Benign according to our data. Variant chr16-3727696-A-G is described in ClinVar as [Benign]. Clinvar id is 1230148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.312 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CREBBP	NM_004380.3	c.*22T>C		3_prime_UTR_variant	31/31	ENST00000262367.10	NP_004371.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CREBBP	ENST00000262367.10	c.*22T>C		3_prime_UTR_variant	31/31	1	NM_004380.3	ENSP00000262367	P1
CREBBP	ENST00000382070.7	c.*22T>C		3_prime_UTR_variant	30/30	1		ENSP00000371502

Frequencies

GnomAD3 genomes AF: 0.0922 AC: 14004 AN: 151904 Hom.: 2135 Cov.: 31

Gnomad AFR AF: 0.316

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0422

Gnomad ASJ AF: 0.0182

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00146

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00153

Gnomad OTH AF: 0.0656

GnomAD3 exomes AF: 0.0258 AC: 6473 AN: 251332 Hom.: 903 AF XY: 0.0187 AC XY: 2543 AN XY: 135874

Gnomad AFR exome AF: 0.332

Gnomad AMR exome AF: 0.0194

Gnomad ASJ exome AF: 0.0130

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00160

Gnomad OTH exome AF: 0.0145

GnomAD4 exome AF: 0.0104 AC: 15247 AN: 1461542 Hom.: 1910 Cov.: 32 AF XY: 0.00909 AC XY: 6608 AN XY: 727096

Gnomad4 AFR exome AF: 0.330

Gnomad4 AMR exome AF: 0.0220

Gnomad4 ASJ exome AF: 0.0151

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000835

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.00104

Gnomad4 OTH exome AF: 0.0243

GnomAD4 genome AF: 0.0925 AC: 14062 AN: 152022 Hom.: 2151 Cov.: 31 AF XY: 0.0883 AC XY: 6566 AN XY: 74322

Gnomad4 AFR AF: 0.316

Gnomad4 AMR AF: 0.0422

Gnomad4 ASJ AF: 0.0182

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00146

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00153

Gnomad4 OTH AF: 0.0649

Alfa AF: 0.0575 Hom.: 322

Bravo AF: 0.107

Asia WGS AF: 0.0240 AC: 85 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	-0.69
CADD	Benign	6.8
DANN	Benign	0.69

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: rs2230140; hg19: chr16-3777697;