chr16-3729114-T-A

Position:

• chr16-3729114-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_004380.3(CREBBP):​c.5933A>T​(p.Asn1978Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,429,802 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1978K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: CREBBP NM_004380.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.38

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CREBBP. . Gene score misZ 3.8991 (greater than the threshold 3.09). Trascript score misZ 4.7573 (greater than threshold 3.09). GenCC has associacion of gene with Menke-Hennekam syndrome 1, Rubinstein-Taybi syndrome due to CREBBP mutations, Rubinstein-Taybi syndrome.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CREBBP	NM_004380.3	c.5933A>T	p.Asn1978Ile	missense_variant	31/31	ENST00000262367.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CREBBP	ENST00000262367.10	c.5933A>T	p.Asn1978Ile	missense_variant	31/31	1	NM_004380.3	P1
CREBBP	ENST00000382070.7	c.5819A>T	p.Asn1940Ile	missense_variant	30/30	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000494 AC: 1 AN: 202582 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 110892

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000368

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.99e-7 AC: 1 AN: 1429802 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 710260

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000831 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Benign	0.85
DEOGEN2	Uncertain	0.55	D;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.042
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.0	L;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.5	D;D
REVEL	Uncertain	0.34
Sift	Benign	0.18	T;T
Sift4G	Benign	0.47	T;T
Polyphen		0.0	B;.
Vest4		0.61
MutPred		0.50		Gain of sheet (P = 0.0061);.;
MVP		0.88
MPC		0.48
ClinPred		0.20	T
GERP RS		5.0
Varity_R		0.23
gMVP		0.40

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: rs112906840; hg19: chr16-3779115;