rs138944476

chr8-41934112-C-Achr8-41934112-C-Gchr8-41934112-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_006766.5(KAT6A):c.4108G>T(p.Glu1370Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KAT6A NM_006766.5 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 2.60

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 10 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 25 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	UniProt
KAT6A	NM_006766.5	c.4108G>T	p.Glu1370Ter	stop_gained	17/17	ENST00000265713.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KAT6A	ENST00000265713.8	c.4108G>T	p.Glu1370Ter	stop_gained	17/17	1	NM_006766.5	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 05, 2015

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 08, 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).;p.Glu1370Stop (GAG>TAG): c.4108 G>T in exon 18 in the KAT6A gene (NM_001099412.1). The E1370X nonsense variant in the KAT6A gene has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. E1370X is predicted to cause loss of normal protein function through protein truncation. E1370X creates a new stop codon on the last exon of the KAT6A gene, resulting in loss of the last 635 amnio acids in the resulting protein. This finding requires further evaluation in a research setting. This variant has been seen de novo. The variant is found in KAT6A panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
Cadd	Pathogenic	35
Dann	Uncertain	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D
Vest4		0.76, 0.75
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs138944476; hg19: chr8-41791630;