rs786200955

Positions:

• chr8-41934389-G-GAA

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_006766.5(KAT6A):​c.3830_3831insTT​(p.Arg1278SerfsTer17) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KAT6A NM_006766.5 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 2.96

Genes affected

KAT6A (HGNC:13013): (lysine acetyltransferase 6A) This gene encodes a member of the MOZ, YBFR2, SAS2, TIP60 family of histone acetyltransferases. The protein is composed of a nuclear localization domain, a double C2H2 zinc finger domain that binds to acetylated histone tails, a histone acetyl-transferase domain, a glutamate/aspartate-rich region, and a serine- and methionine-rich transactivation domain. It is part of a complex that acetylates lysine-9 residues in histone 3, and in addition, it acts as a co-activator for several transcription factors. Allelic variants of this gene are associated with an autosomal dominant form of cognitive disability. Chromosomal translocations of this gene are associated with acute myeloid leukemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 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 9 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KAT6A	NM_006766.5	c.3830_3831insTT	p.Arg1278SerfsTer17	frameshift_variant	17/17	ENST00000265713.8	NP_006757.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KAT6A	ENST00000265713.8	c.3830_3831insTT	p.Arg1278SerfsTer17	frameshift_variant	17/17	1	NM_006766.5	ENSP00000265713	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 05, 2014

The KAT6A gene is a candidate gene. This variant requires further evaluation in a research setting. To date, no mutations in the KAT6A gene have been reported in association with a specific human disease to our knowledge. However, multiple patients presenting with global developmental delay, dysmorphic facial features, hypotonia, and cardiac anomalies were found to carry a de novo variant in the KAT6A gene at GeneDx. While the function of KAT6A has not been completely defined, studies in mice suggest that KAT6A may act as a chromatin modifier by interacting with the TBX1 gene. Mutations in the TBX1 gene as well as contiguous gene deletions including the TBX1 gene within cytogenetic band 22q11 cause Velocardiofacial/DiGeorge syndrome. KAT6A-null mice have features that mirror the 22q11 deletion syndrome, suggesting KAT6A is involved in cardiac, pharyngeal and facial development (Voss et al., 2012).; p.Arg1278SerfsX17: c.3830_3831insTT in exon 18 in the KAT6A gene (NM_001099412.1). The normal sequence with the bases that are inserted in braces is: GAAGCC{TT}CCGT. The c.3830_3831insTT variant in the KAT6A gene has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. The c.3830_3831insTT variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The c.3830_3831insTT variant causes a frameshift starting with codon Arginine 1278, changes this amino acid to a Serine residue and creates a premature Stop codon at position 17 of the new reading frame, denoted p.Arg1278SerfsX17. This variant is predicted to cause loss of normal protein function through protein truncation. We interpret c.3830_3831insTT as a variant of unknown significance. This variant has been seen de novo. The variant is found in KAT6A panel(s). -

KAT6A-related neurodevelopmental disorder with multiple anomalies Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Brain Gene Registry

-

Variant classified as Pathogenic and reported on 01-18-2023 by GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -

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: rs786200955; hg19: chr8-41791907;