8-41932225-C-T

Position:

• chr8-41932225-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP6

The NM_006766.5(KAT6A):​c.5995G>A​(p.Gly1999Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,451,864 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KAT6A NM_006766.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.01

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KAT6A. . Gene score misZ 2.0718 (greater than the threshold 3.09). Trascript score misZ 3.1208 (greater than threshold 3.09). GenCC has associacion of gene with syndromic intellectual disability, autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome.
• BP6: Variant 8-41932225-C-T is Benign according to our data. Variant chr8-41932225-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1750920.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KAT6A	NM_006766.5	c.5995G>A	p.Gly1999Arg	missense_variant	17/17	ENST00000265713.8	NP_006757.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KAT6A	ENST00000265713.8	c.5995G>A	p.Gly1999Arg	missense_variant	17/17	1	NM_006766.5	ENSP00000265713.2
KAT6A	ENST00000406337.6	c.6001G>A	p.Gly2001Arg	missense_variant	18/18	5		ENSP00000385888.2
KAT6A	ENST00000396930.4	c.5995G>A	p.Gly1999Arg	missense_variant	18/18	5		ENSP00000380136.3
KAT6A	ENST00000649817.1	c.4675G>A	p.Gly1559Arg	missense_variant	11/11			ENSP00000497780.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000820 AC: 2 AN: 243926 Hom.: 0 AF XY: 0.0000152 AC XY: 2 AN XY: 131732

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000341

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1451864 Hom.: 0 Cov.: 32 AF XY: 0.00000277 AC XY: 2 AN XY: 721444

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 12, 2018

The p.G1999R variant (also known as c.5995G>A), located in coding exon 16 of the KAT6A gene, results from a G to A substitution at nucleotide position 5995. The glycine at codon 1999 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 05, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	.;T;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	D;.;D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.57	D;D;D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	0.69	.;N;N
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.6	.;D;D
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	.;D;D
Sift4G	Pathogenic	0.0010	.;D;D
Polyphen		1.0	.;D;D
Vest4		0.89, 0.90
MutPred		0.27		.;Gain of MoRF binding (P = 0.0534);Gain of MoRF binding (P = 0.0534);
MVP		0.79
MPC		0.22
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.41
gMVP		0.46

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: rs753662262; hg19: chr8-41789743;