8-41933987-CTCTTT-C

Variant names:

• chr8-41933987-CTCTTT-C
• rs1554679889
• NM_006766.5:c.4228_4232delAAAGA

Variant summary

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

The NM_006766.5(KAT6A):​c.4228_4232delAAAGA​(p.Lys1410GlyfsTer7) variant causes a frameshift change. 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: KAT6A NM_006766.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 5.75

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 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 6 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-41933987-CTCTTT-C is Pathogenic according to our data. Variant chr8-41933987-CTCTTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 524135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KAT6A	NM_006766.5	c.4228_4232delAAAGA	p.Lys1410GlyfsTer7	frameshift_variant	Exon 17 of 17	ENST00000265713.8	NP_006757.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KAT6A	ENST00000265713.8	c.4228_4232delAAAGA	p.Lys1410GlyfsTer7	frameshift_variant	Exon 17 of 17	1	NM_006766.5	ENSP00000265713.2

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome Pathogenic:2

Nov 05, 2021

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 13, 2018

Genomic Medicine Lab, University of California San Francisco

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Jul 27, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4228_4232delAAAGA pathogenic mutation (also known as p.K1410GFS*7), located in coding exon 16 of the KAT6A gene, results from a deletion of 5 nucleotides at nucleotide positions 4228 to 4232, causing a translational frameshift with a predicted alternate stop codon. This mutation is located downstream of the nonsense-mediated mRNA decay (NMD) boundary. Typically, mRNA transcripts from alterations located downstream of NMD boundaries will not be degraded, resulting in translation of a truncated protein. A de novo protein truncating variant (c.4292dupT), located downstream of the c.4228_4232delAAAGA pathogenic mutation, has been reported in an individual presenting with global developmental delay, significant hypotonia, cardiac defects and dysmorphic features (Tham E et al. Am J Hum Genet. 2015; 96(3):507-13). Therefore, both alterations likely escape NMD and are expected to result in loss of function by premature protein truncation. As such, the c.4228_4232delAAAGA alteration is interpreted as a disease-causing mutation -

See cases Pathogenic:1

Dec 21, 2022

Center for Personalized Medicine, Children's Hospital Los Angeles

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Nov 10, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in a patient with intellectual disability and speech delay in the published literature (Kennedy et al., 2019); Frameshift variant predicted to result in protein truncation, as the last 595 amino acids are replaced with 6 different amino acids; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30245513) -

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: rs1554679889; hg19: chr8-41791505;