rs3740321

Positions:

• chr10-75029319-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_012330.4(KAT6B):​c.4495G>A​(p.Val1499Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0178 in 1,614,038 control chromosomes in the GnomAD database, including 685 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1499T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.032 (142 hom., cov: 32)
  • Exomes 𝑓: 0.016 (543 hom.)
• Consequence: KAT6B NM_012330.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 6.03

Genes affected

KAT6B (HGNC:17582): (lysine acetyltransferase 6B) The protein encoded by this gene is a histone acetyltransferase and component of the MOZ/MORF protein complex. In addition to its acetyltransferase activity, the encoded protein has transcriptional activation activity in its N-terminal end and transcriptional repression activity in its C-terminal end. This protein is necessary for RUNX2-dependent transcriptional activation and could be involved in brain development. Mutations have been found in patients with genitopatellar syndrome. A translocation of this gene and the CREBBP gene results in acute myeloid leukemias. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KAT6B
• BP4: Computational evidence support a benign effect (MetaRNN=0.0019197166).
• BP6: Variant 10-75029319-G-A is Benign according to our data. Variant chr10-75029319-G-A is described in ClinVar as [Benign]. Clinvar id is 260246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-75029319-G-A is described in Lovd as [Benign]. Variant chr10-75029319-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0756 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KAT6B	NM_012330.4	c.4495G>A	p.Val1499Ile	missense_variant	18/18	ENST00000287239.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KAT6B	ENST00000287239.10	c.4495G>A	p.Val1499Ile	missense_variant	18/18	1	NM_012330.4	P2

Frequencies

GnomAD3 genomes AF: 0.0324 AC: 4920 AN: 152032 Hom.: 142 Cov.: 32

Gnomad AFR AF: 0.0576

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0446

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.0821

Gnomad SAS AF: 0.0285

Gnomad FIN AF: 0.0332

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0114

Gnomad OTH AF: 0.0335

GnomAD3 exomes AF: 0.0349 AC: 8755 AN: 251050 Hom.: 300 AF XY: 0.0316 AC XY: 4289 AN XY: 135714

Gnomad AFR exome AF: 0.0567

Gnomad AMR exome AF: 0.0853

Gnomad ASJ exome AF: 0.0216

Gnomad EAS exome AF: 0.0854

Gnomad SAS exome AF: 0.0278

Gnomad FIN exome AF: 0.0324

Gnomad NFE exome AF: 0.0118

Gnomad OTH exome AF: 0.0341

GnomAD4 exome AF: 0.0163 AC: 23770 AN: 1461888 Hom.: 543 Cov.: 35 AF XY: 0.0163 AC XY: 11825 AN XY: 727246

Gnomad4 AFR exome AF: 0.0636

Gnomad4 AMR exome AF: 0.0781

Gnomad4 ASJ exome AF: 0.0235

Gnomad4 EAS exome AF: 0.0679

Gnomad4 SAS exome AF: 0.0257

Gnomad4 FIN exome AF: 0.0316

Gnomad4 NFE exome AF: 0.00825

Gnomad4 OTH exome AF: 0.0234

GnomAD4 genome AF: 0.0323 AC: 4922 AN: 152150 Hom.: 142 Cov.: 32 AF XY: 0.0337 AC XY: 2508 AN XY: 74400

Gnomad4 AFR AF: 0.0576

Gnomad4 AMR AF: 0.0444

Gnomad4 ASJ AF: 0.0222

Gnomad4 EAS AF: 0.0821

Gnomad4 SAS AF: 0.0283

Gnomad4 FIN AF: 0.0332

Gnomad4 NFE AF: 0.0114

Gnomad4 OTH AF: 0.0326

Alfa AF: 0.0181 Hom.: 117

Bravo AF: 0.0366

TwinsUK AF: 0.00890 AC: 33

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.0486 AC: 214

ESP6500EA AF: 0.0123 AC: 106

ExAC AF: 0.0327 AC: 3967

Asia WGS AF: 0.0580 AC: 200 AN: 3478

EpiCase AF: 0.0141

EpiControl AF: 0.0147

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Genitopatellar syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	16
DANN	Benign	0.66
DEOGEN2	Benign	0.097	T;.;T;.;.;.;.;T;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.75	D
MetaRNN	Benign	0.0019	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.7	L;.;L;.;.;.;.;L;.
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.31	T
Polyphen		0.017	B;B;B;B;B;B;B;B;B
Vest4		0.086, 0.090, 0.057, 0.012
MPC		0.17
ClinPred		0.027	T
GERP RS		4.8
Varity_R		0.060
gMVP		0.029

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: rs3740321; hg19: chr10-76789077; COSMIC: COSV54747216; COSMIC: COSV54747216;