rs199470477

Variant names:

• chr10-75029026-ACT-A
• rs199470477
• NM_012330.4:c.4205_4206delCT

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_012330.4(KAT6B):​c.4205_4206delCT​(p.Ser1402CysfsTer5) variant causes a frameshift change involving the alteration of a non-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:7 O:2
• Conservation: PhyloP100: -0.140

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 14 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 18 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-75029026-ACT-A is Pathogenic according to our data. Variant chr10-75029026-ACT-A is described in ClinVar as [Pathogenic]. Clinvar id is 39001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-75029026-ACT-A is described in Lovd as [Likely_pathogenic]. Variant chr10-75029026-ACT-A is described in Lovd as [Likely_pathogenic]. Variant chr10-75029026-ACT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KAT6B	NM_012330.4	c.4205_4206delCT	p.Ser1402CysfsTer5	frameshift_variant	Exon 18 of 18	ENST00000287239.10	NP_036462.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KAT6B	ENST00000287239.10	c.4205_4206delCT	p.Ser1402CysfsTer5	frameshift_variant	Exon 18 of 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:7 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Genitopatellar syndrome Pathogenic:3

Feb 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 39001). This premature translational stop signal has been observed in individual(s) with genitopatellar syndrome or Say-Barber-Biesecker-Young-Simpson syndrome and KAT6B-related conditions (PMID: 22077973, 25424711, 28696035; 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.Ser1402Cysfs*5) in the KAT6B gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 672 amino acid(s) of the KAT6B protein. -

Aug 19, 2019

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 25, 2023

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The heterozygous p.Ser1402CysfsTer5 variant in KAT6B was identified by our study in one individual with microcephaly, agenesis of the corpus callosum, and global developmental delay. Trio exome analysis showed this variant to be de novo. This variant was found to be de novo in 6 individuals with confirmed paternity and maternity (PMID: 28696035, PMID: 22077973, PMID: 25424711, SCV001150140.1, SCV001364303.1). This variant is assumed de novo in 2 individuals, but maternity and paternity have not been confirmed (PMID: 25424711, PMID: 22077973). The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant has also been reported in ClinVar (Variation ID: 39001) and has been interpreted as pathogenic by multiple submitters. This variant was absent from large population studies.This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1402 and leads to a premature termination codon 5 amino acids downstream. This termination codon occurs within the terminal 50 bases of the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Heterozygous loss of function of the KAT6B gene is an established disease mechanism in autosomal dominant genitopatellar syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant genitopatellar syndrome. ACMG/AMP Criteria applied: PVS1_Strong, PS2_VeryStrong, PS4, PM2_Supporting (Richards 2015). -

not provided Pathogenic:1 Other:1

-

Lee Lab(KAT6B), Baylor College of Medicine

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Oct 30, 2019

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 672 amino acids are lost and replaced with 4 incorrect amino acids (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 22077973, 28696035) -

Inborn genetic diseases Pathogenic:1

Apr 01, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genitopatellar syndrome;C4551957:Epilepsy, familial temporal lobe, 1 Pathogenic:1

Apr 04, 2022

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genitopatellar syndrome;C1863557:Blepharophimosis - intellectual disability syndrome, SBBYS type Pathogenic:1

Feb 28, 2025

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Blepharophimosis - intellectual disability syndrome, SBBYS type Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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: rs199470477; hg19: chr10-76788784;