rs199470480

chr10-75029723-AAGTGCCATCTC-A

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.4911_4921del(p.Val1638AlafsTer27) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KAT6B NM_012330.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 7.67

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 35 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-75029723-AAGTGCCATCTC-A is Pathogenic according to our data. Variant chr10-75029723-AAGTGCCATCTC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 140476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-75029723-AAGTGCCATCTC-A is described in Lovd as [Likely_pathogenic]. Variant chr10-75029723-AAGTGCCATCTC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KAT6B	NM_012330.4	c.4911_4921del	p.Val1638AlafsTer27	frameshift_variant	18/18	ENST00000287239.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KAT6B	ENST00000287239.10	c.4911_4921del	p.Val1638AlafsTer27	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/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 23, 2019	The c.4911_4921del11 variant in the KAT6B gene has been reported previously as a presumed de novo finding in an individual with Say-Barber-Biesecker-Young-Simpson (Clayton et al., 2011). The c.4911_4921del11 variant causes a frameshift starting with codon Valine 1638, changes this amino acid to an Alanine residue, and creates a premature Stop codon at position 27 of the new reading frame, denoted p.Val1638AlafsX27. This variant is predicted to cause loss of normal protein function through protein truncation. The c.4911_4921del11 variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.4911_4921del11 as a pathogenic variant. -
not provided, no classification provided	literature only	Lee Lab(KAT6B), Baylor College of Medicine	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2021	- -

Blepharophimosis - intellectual disability syndrome, SBBYS type Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199470480; hg19: chr10-76789481;