10-74842897-C-A

Variant names:

• chr10-74842897-C-A
• NM_012330.4:c.40C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_012330.4(KAT6B):​c.40C>A​(p.Leu14Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 7.57

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KAT6B	NM_012330.4	c.40C>A	p.Leu14Ile	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.40C>A	p.Leu14Ile	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

Aug 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 14 of the KAT6B protein (p.Leu14Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KAT6B-related conditions. 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 with a negative predictive value of 80%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	.;T;.;.;T;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;.;.
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.060	D
MetaRNN	Uncertain	0.62	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Uncertain	2.6	.;M;.;M;M;M;.;.;.;.;.;M;.;M;.;M;M;.;.;.;.;.;.;M;.;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.9	.;.;.;.;.;N;.;.;.;.;.;.;.;N;.;N;N;.;.;.;.;.;.;N;.;.
REVEL	Uncertain	0.47
Sift	Uncertain	0.016	.;.;.;.;.;D;.;.;.;.;.;.;.;D;.;D;D;.;.;.;.;.;.;D;.;.
Sift4G	Pathogenic	0.0	.;.;.;.;.;D;.;.;.;.;.;.;.;D;.;D;D;.;.;.;.;.;.;D;.;.
Polyphen		1.0, 1.0	.;D;.;D;D;D;.;.;.;.;.;D;.;D;.;D;D;.;.;.;.;.;.;D;.;.
Vest4		0.73, 0.70, 0.72, 0.73, 0.69
MutPred		0.30		Gain of MoRF binding (P = 0.1277);Gain of MoRF binding (P = 0.1277);Gain of MoRF binding (P = 0.1277);Gain of MoRF binding (P = 0.1277);Gain of MoRF binding (P = 0.1277);Gain of MoRF binding (P = 0.1277);Gain of MoRF binding (P = 0.1277);Gain of MoRF binding (P = 0.1277);Gain of MoRF binding (P = 0.1277);Gain of MoRF binding (P = 0.1277);Gain of MoRF binding (P = 0.1277);Gain of MoRF binding (P = 0.1277);Gain of MoRF binding (P = 0.1277);Gain of MoRF binding (P = 0.1277);Gain of MoRF binding (P = 0.1277);Gain of MoRF binding (P = 0.1277);Gain of MoRF binding (P = 0.1277);Gain of MoRF binding (P = 0.1277);Gain of MoRF binding (P = 0.1277);Gain of MoRF binding (P = 0.1277);Gain of MoRF binding (P = 0.1277);Gain of MoRF binding (P = 0.1277);Gain of MoRF binding (P = 0.1277);Gain of MoRF binding (P = 0.1277);Gain of MoRF binding (P = 0.1277);Gain of MoRF binding (P = 0.1277);
MVP		0.87
MPC		1.0
ClinPred		0.97	D
GERP RS		6.2
Varity_R		0.20
gMVP		0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-76602655;