rs199470472

chr10-75028610-CAA-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_012330.4(KAT6B):c.3788_3789del(p.Lys1263ArgfsTer7) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KAT6B NM_012330.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 8.28

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 68 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-75028610-CAA-C is Pathogenic according to our data. Variant chr10-75028610-CAA-C is described in ClinVar as [Pathogenic]. Clinvar id is 140472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-75028610-CAA-C is described in Lovd as [Pathogenic]. Variant chr10-75028610-CAA-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KAT6B	NM_012330.4	c.3788_3789del	p.Lys1263ArgfsTer7	frameshift_variant	18/18	ENST00000287239.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KAT6B	ENST00000287239.10	c.3788_3789del	p.Lys1263ArgfsTer7	frameshift_variant	18/18	1	NM_012330.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Genitopatellar syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 26, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 140472). This premature translational stop signal has been observed in individual(s) with clinical features of genitopatellar syndrome (PMID: 22265014, 32424177; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys1263Argfs*7) in the KAT6B gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 811 amino acid(s) of the KAT6B protein. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 10, 2012	- -

not provided Pathogenic:1 Other:1

not provided, no classification provided	literature only	Lee Lab(KAT6B), Baylor College of Medicine	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2021	Frameshift variant predicted to result in protein truncation, as the last 811 amino acids are replaced with 6 different amino acids; other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 23436491, 32424177, 22265014, 22715153) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 04, 2018

- -

Computational scores

Source: dbNSFP v4.3

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: rs199470472; hg19: chr10-76788368;