8-41932246-C-G

Variant names:

• chr8-41932246-C-G
• rs1050612463
• NM_006766.5:c.5974G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006766.5(KAT6A):​c.5974G>C​(p.Val1992Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: KAT6A NM_006766.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.23

Genes affected

KAT6A (HGNC:13013): (lysine acetyltransferase 6A) This gene encodes a member of the MOZ, YBFR2, SAS2, TIP60 family of histone acetyltransferases. The protein is composed of a nuclear localization domain, a double C2H2 zinc finger domain that binds to acetylated histone tails, a histone acetyl-transferase domain, a glutamate/aspartate-rich region, and a serine- and methionine-rich transactivation domain. It is part of a complex that acetylates lysine-9 residues in histone 3, and in addition, it acts as a co-activator for several transcription factors. Allelic variants of this gene are associated with an autosomal dominant form of cognitive disability. Chromosomal translocations of this gene are associated with acute myeloid leukemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3661418).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KAT6A	NM_006766.5	c.5974G>C	p.Val1992Leu	missense_variant	Exon 17 of 17	ENST00000265713.8	NP_006757.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KAT6A	ENST00000265713.8	c.5974G>C	p.Val1992Leu	missense_variant	Exon 17 of 17	1	NM_006766.5	ENSP00000265713.2
KAT6A	ENST00000406337.6	c.5980G>C	p.Val1994Leu	missense_variant	Exon 18 of 18	5		ENSP00000385888.2
KAT6A	ENST00000396930.4	c.5974G>C	p.Val1992Leu	missense_variant	Exon 18 of 18	5		ENSP00000380136.3
KAT6A	ENST00000649817.1	c.4654G>C	p.Val1552Leu	missense_variant	Exon 11 of 11			ENSP00000497780.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 20, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The V1992L variant in the KAT6A gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The V1992L variant is not observed in large population cohorts (Lek et al., 2016). The V1992L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret V1992L as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Benign	0.91
DEOGEN2	Benign	0.15	.;T;T
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;.;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.37	T;T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	0.0	.;N;N
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.68	.;N;N
REVEL	Benign	0.23
Sift	Uncertain	0.0080	.;D;D
Sift4G	Uncertain	0.032	.;D;D
Polyphen		1.0	.;D;D
Vest4		0.56, 0.65
MutPred		0.19		.;Loss of MoRF binding (P = 0.0957);Loss of MoRF binding (P = 0.0957);
MVP		0.51
MPC		0.18
ClinPred		0.78	D
GERP RS		5.9
Varity_R		0.14
gMVP		0.56

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: rs1050612463; hg19: chr8-41789764;