10-75028701-A-G

Variant names:

• chr10-75028701-A-G
• rs199470474
• NM_012330.4:c.3877A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012330.4(KAT6B):​c.3877A>G​(p.Lys1293Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KAT6B NM_012330.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.99
• Publications: 0 publications found

Genes affected

KAT6B (HGNC:17582): (lysine acetyltransferase 6B) The protein encoded by this gene is a histone acetyltransferase and component of the MOZ/MORF protein complex. In addition to its acetyltransferase activity, the encoded protein has transcriptional activation activity in its N-terminal end and transcriptional repression activity in its C-terminal end. This protein is necessary for RUNX2-dependent transcriptional activation and could be involved in brain development. Mutations have been found in patients with genitopatellar syndrome. A translocation of this gene and the CREBBP gene results in acute myeloid leukemias. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2012]

KAT6B Gene-Disease associations (from GenCC):

• blepharophimosis - intellectual disability syndrome, SBBYS type

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• genitopatellar syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• KAT6B-related multiple congenital anomalies syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• multiple congenital anomalies/dysmorphic syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• RASopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1327717).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012330.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KAT6B	NM_012330.4	MANE Select	c.3877A>G	p.Lys1293Glu	missense	Exon 18 of 18	NP_036462.2	Q8WYB5-1
	KAT6B	NM_001370136.1		c.3877A>G	p.Lys1293Glu	missense	Exon 18 of 18	NP_001357065.1	Q8WYB5-1
	KAT6B	NM_001370137.1		c.3877A>G	p.Lys1293Glu	missense	Exon 18 of 18	NP_001357066.1	Q8WYB5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KAT6B	ENST00000287239.10	TSL:1 MANE Select	c.3877A>G	p.Lys1293Glu	missense	Exon 18 of 18	ENSP00000287239.4	Q8WYB5-1
	KAT6B	ENST00000372711.2	TSL:1	c.3328A>G	p.Lys1110Glu	missense	Exon 18 of 18	ENSP00000361796.1	Q8WYB5-2
	KAT6B	ENST00000648725.1		c.3877A>G	p.Lys1293Glu	missense	Exon 18 of 18	ENSP00000497841.1	Q8WYB5-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Genitopatellar syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.062	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.064
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.0
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.24
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.28	T
Polyphen		0.026	B
Vest4		0.31
MutPred		0.31		Loss of ubiquitination at K1293 (P = 3e-04)
MVP		0.22
MPC		0.29
ClinPred		0.32	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.25
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

dbSNP: rs199470474; hg19: chr10-76788459;