NM_012330.4:c.293C>T

Variant names:

• chr10-74843150-C-T
• NM_012330.4:c.293C>T

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.293C>T​(p.Ser98Leu) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S98T) has been classified 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: 2.84
• 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
• 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=0.17588642).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KAT6B	NM_012330.4	c.293C>T	p.Ser98Leu	missense_variant	Exon 3 of 18	ENST00000287239.10	NP_036462.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KAT6B	ENST00000287239.10	c.293C>T	p.Ser98Leu	missense_variant	Exon 3 of 18	1	NM_012330.4	ENSP00000287239.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Genitopatellar syndrome Uncertain:1

Jul 28, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 98 of the KAT6B protein (p.Ser98Leu). This variant has not been reported in the literature in individuals affected with KAT6B-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KAT6B protein function. ClinVar contains an entry for this variant (Variation ID: 2134166). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Benign	0.21	T;.;.;T;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;.
Eigen	Benign	-0.010
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.1	L;.;L;L;L;.;.;.;.;.;L;L;.;L;L;.;.;.;.;.;.;L;.
PhyloP100		2.8
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-2.3	.;.;.;.;N;.;.;.;.;.;.;N;.;N;N;.;.;.;.;.;.;N;.
REVEL	Benign	0.24
Sift	Benign	0.21	.;.;.;.;T;.;.;.;.;.;.;T;.;T;D;.;.;.;.;.;.;T;.
Sift4G	Uncertain	0.052	.;.;.;.;T;.;.;.;.;.;.;T;.;T;T;.;.;.;.;.;.;T;.
Polyphen		0.013	B;.;B;B;B;.;.;.;.;.;B;B;.;B;B;.;.;.;.;.;.;B;.
Vest4		0.19, 0.18, 0.22, 0.15, 0.12
MutPred		0.17		Loss of phosphorylation at S98 (P = 0.0255);Loss of phosphorylation at S98 (P = 0.0255);Loss of phosphorylation at S98 (P = 0.0255);Loss of phosphorylation at S98 (P = 0.0255);Loss of phosphorylation at S98 (P = 0.0255);Loss of phosphorylation at S98 (P = 0.0255);Loss of phosphorylation at S98 (P = 0.0255);Loss of phosphorylation at S98 (P = 0.0255);Loss of phosphorylation at S98 (P = 0.0255);Loss of phosphorylation at S98 (P = 0.0255);Loss of phosphorylation at S98 (P = 0.0255);Loss of phosphorylation at S98 (P = 0.0255);Loss of phosphorylation at S98 (P = 0.0255);Loss of phosphorylation at S98 (P = 0.0255);Loss of phosphorylation at S98 (P = 0.0255);Loss of phosphorylation at S98 (P = 0.0255);Loss of phosphorylation at S98 (P = 0.0255);Loss of phosphorylation at S98 (P = 0.0255);Loss of phosphorylation at S98 (P = 0.0255);Loss of phosphorylation at S98 (P = 0.0255);Loss of phosphorylation at S98 (P = 0.0255);Loss of phosphorylation at S98 (P = 0.0255);Loss of phosphorylation at S98 (P = 0.0255);
MVP		0.24
MPC		0.33
ClinPred		0.31	T
GERP RS		6.2
Varity_R		0.10
gMVP		0.31
Mutation Taster		=86/14	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

hg19: chr10-76602908;