rs144417514

Positions:

• chr8-41933268-G-A

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.4952C>T​(p.Pro1651Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 1,565,254 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (3 hom.)
• Consequence: KAT6A NM_006766.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.516

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 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0101650655).
• BP6: Variant 8-41933268-G-A is Benign according to our data. Variant chr8-41933268-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 445624.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41933268-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 206 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KAT6A	NM_006766.5	c.4952C>T	p.Pro1651Leu	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.4952C>T	p.Pro1651Leu	missense_variant	17/17	1	NM_006766.5	ENSP00000265713.2

Frequencies

GnomAD3 genomes AF: 0.00136 AC: 206 AN: 151584 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00204

Gnomad ASJ AF: 0.000578

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00211

Gnomad OTH AF: 0.000483

GnomAD3 exomes AF: 0.00124 AC: 229 AN: 183942 Hom.: 0 AF XY: 0.00114 AC XY: 113 AN XY: 98968

Gnomad AFR exome AF: 0.000326

Gnomad AMR exome AF: 0.000439

Gnomad ASJ exome AF: 0.000941

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00205

Gnomad NFE exome AF: 0.00223

Gnomad OTH exome AF: 0.000616

GnomAD4 exome AF: 0.00177 AC: 2505 AN: 1413558 Hom.: 3 Cov.: 36 AF XY: 0.00169 AC XY: 1180 AN XY: 699934

Gnomad4 AFR exome AF: 0.000548

Gnomad4 AMR exome AF: 0.000585

Gnomad4 ASJ exome AF: 0.000779

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000248

Gnomad4 FIN exome AF: 0.00182

Gnomad4 NFE exome AF: 0.00210

Gnomad4 OTH exome AF: 0.00124

GnomAD4 genome AF: 0.00136 AC: 206 AN: 151696 Hom.: 0 Cov.: 32 AF XY: 0.00120 AC XY: 89 AN XY: 74152

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.000578

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00211

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.00190 Hom.: 0

Bravo AF: 0.00155

ESP6500AA AF: 0.000471 AC: 2

ESP6500EA AF: 0.00171 AC: 14

ExAC AF: 0.000852 AC: 102

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:7

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 17, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 20, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	KAT6A: BS1 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

KAT6A-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 29, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 07, 2018

This alteration is classified as likely 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	0.12
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	12
DANN	Benign	0.69
DEOGEN2	Benign	0.11	.;T;T;.
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.59	T;.;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.010	T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.81	.;L;L;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.4	N;N;N;.
REVEL	Benign	0.035
Sift	Uncertain	0.0060	D;D;D;.
Sift4G	Benign	0.075	.;T;T;.
Polyphen		0.10	.;B;B;.
Vest4		0.39, 0.36
MVP		0.29
MPC		0.19
ClinPred		0.010	T
GERP RS		3.5
Varity_R		0.070
gMVP		0.11

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: rs144417514; hg19: chr8-41790786;