8-41932236-T-C

Variant names:

• chr8-41932236-T-C
• NM_006766.5:c.5984A>G

Variant summary

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

The NM_006766.5(KAT6A):​c.5984A>G​(p.Gln1995Arg) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1995P) has been classified 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: 7.86

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=0.41448674).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KAT6A	NM_006766.5	c.5984A>G	p.Gln1995Arg	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.5984A>G	p.Gln1995Arg	missense_variant	Exon 17 of 17	1	NM_006766.5	ENSP00000265713.2
KAT6A	ENST00000406337.6	c.5990A>G	p.Gln1997Arg	missense_variant	Exon 18 of 18	5		ENSP00000385888.2
KAT6A	ENST00000396930.4	c.5984A>G	p.Gln1995Arg	missense_variant	Exon 18 of 18	5		ENSP00000380136.3
KAT6A	ENST00000649817.1	c.4664A>G	p.Gln1555Arg	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

Inborn genetic diseases Uncertain:1

Feb 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q1995R variant (also known as c.5984A>G), located in coding exon 16 of the KAT6A gene, results from an A to G substitution at nucleotide position 5984. The glutamine at codon 1995 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Uncertain	0.56	.;D;D
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D;.;D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.41	T;T;T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	0.81	.;L;L
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.8	.;D;D
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	.;D;D
Sift4G	Pathogenic	0.0	.;D;D
Polyphen		0.99	.;D;D
Vest4		0.78, 0.66
MutPred		0.17		.;Gain of MoRF binding (P = 0.0236);Gain of MoRF binding (P = 0.0236);
MVP		0.73
MPC		0.20
ClinPred		0.57	D
GERP RS		5.9
Varity_R		0.69
gMVP		0.84

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: chr8-41789754;