rs199470472

Positions:

• 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_3789delAA​(p.Lys1263fs) 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 27 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	Protein	UniProt
KAT6B	NM_012330.4	c.3788_3789delAA	p.Lys1263fs	frameshift_variant	18/18	ENST00000287239.10	NP_036462.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KAT6B	ENST00000287239.10	c.3788_3789delAA	p.Lys1263fs	frameshift_variant	18/18	1	NM_012330.4	ENSP00000287239.4

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, no assertion criteria provided	literature only	OMIM	Feb 10, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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. -

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;