rs113195648

chr8-41933896-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_006766.5(KAT6A):c.4324G>A(p.Ala1442Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,614,088 control chromosomes in the GnomAD database, including 103 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (4 hom., cov: 32)
  • Exomes 𝑓: 0.010 (99 hom.)
• Consequence: KAT6A NM_006766.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.16

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 Benign. Variant got -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KAT6A
• BP4: Computational evidence support a benign effect (MetaRNN=0.0064100027).
• BP6: Variant 8-41933896-C-T is Benign according to our data. Variant chr8-41933896-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 445863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 1088 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KAT6A	NM_006766.5	c.4324G>A	p.Ala1442Thr	missense_variant	17/17	ENST00000265713.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KAT6A	ENST00000265713.8	c.4324G>A	p.Ala1442Thr	missense_variant	17/17	1	NM_006766.5	A2

Frequencies

GnomAD3 genomes AF: 0.00715 AC: 1088 AN: 152134 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0109

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0122

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00754 AC: 1891 AN: 250940 Hom.: 9 AF XY: 0.00775 AC XY: 1052 AN XY: 135666

Gnomad AFR exome AF: 0.00247

Gnomad AMR exome AF: 0.00205

Gnomad ASJ exome AF: 0.00517

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00520

Gnomad FIN exome AF: 0.0105

Gnomad NFE exome AF: 0.0114

Gnomad OTH exome AF: 0.00736

GnomAD4 exome AF: 0.0104 AC: 15248 AN: 1461836 Hom.: 99 Cov.: 35 AF XY: 0.0103 AC XY: 7489 AN XY: 727216

Gnomad4 AFR exome AF: 0.00215

Gnomad4 AMR exome AF: 0.00208

Gnomad4 ASJ exome AF: 0.00451

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00547

Gnomad4 FIN exome AF: 0.0125

Gnomad4 NFE exome AF: 0.0120

Gnomad4 OTH exome AF: 0.00786

GnomAD4 genome AF: 0.00715 AC: 1088 AN: 152252 Hom.: 4 Cov.: 32 AF XY: 0.00666 AC XY: 496 AN XY: 74432

Gnomad4 AFR AF: 0.00161

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.0109

Gnomad4 NFE AF: 0.0122

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.0103 Hom.: 12

Bravo AF: 0.00612

TwinsUK AF: 0.00944 AC: 35

ALSPAC AF: 0.0109 AC: 42

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.0142 AC: 122

ExAC AF: 0.00752 AC: 913

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0113

EpiControl AF: 0.0106

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 27, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 18, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	KAT6A: BP4, BS1, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 25, 2019

- -

Autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 30, 2021

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 26, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
Cadd	Uncertain	23
Dann	Uncertain	0.98
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T;.;T;D
MetaRNN	Benign	0.0064	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Benign	0.46	T
REVEL	Benign	0.11
Polyphen		0.51	.;P;P;.
Vest4		0.15, 0.14
MVP		0.38
MPC		0.18
ClinPred		0.012	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.055
gMVP		0.18

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: rs113195648; hg19: chr8-41791414;