rs786200956

chr8-41933927-C-CA

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_006766.5(KAT6A):c.4292_4293insT(p.Leu1431PhefsTer8) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KAT6A NM_006766.5 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.13

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 Pathogenic. Variant got 11 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 23 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-41933927-C-CA is Pathogenic according to our data. Variant chr8-41933927-C-CA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 162182.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KAT6A	NM_006766.5	c.4292_4293insT	p.Leu1431PhefsTer8	frameshift_variant	17/17	ENST00000265713.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KAT6A	ENST00000265713.8	c.4292_4293insT	p.Leu1431PhefsTer8	frameshift_variant	17/17	1	NM_006766.5	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 2016

The c.4292dupT variant, located in coding exon 16 of the KAT6A gene, results from a duplication of T at nucleotide position 4292, causing a translational frameshift with a predicted alternate stop codon. This alteration was detected as a de novo occurrence in an individual with global developmental delay, speech delay, neonatal hypotonia, crainofacial features, and eye and feeding problems (Tham E et al. Am. J. Hum. Genet., 2015 Mar;96:507-13). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This nucleotide position is highly conserved in available vertebrate species. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 06, 2013

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).;c.4292dupT: p.Leu1431PhefsX8 (L1431FfsX8) in exon 18 in the KAT6A gene (NM_001099412.1). The normal sequence with the base that is duplicated in braces is: TCTT{T}GACT. The apparently c.4292dupT variant in the KAT6A gene has not been reported previously, to our knowledge. This variant causes a frameshift starting with codon Leucine 1431, changes this amino acid to a Phenylalanine residue and creates a premature Stop codon at position 8 of the new reading frame, denoted p.Leu1431PhefsX8. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This variant has been seen de novo. The variant is found in KAT6A panel(s). -

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: rs786200956; hg19: chr8-41791445;