rs786200960
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_006766.5(KAT6A):c.3385C>T(p.Arg1129Ter) 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 Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
KAT6A
NM_006766.5 stop_gained
NM_006766.5 stop_gained
Scores
2
2
3
Clinical Significance
Conservation
PhyloP100: 1.22
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 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 43 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 8-41934835-G-A is Pathogenic according to our data. Variant chr8-41934835-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 180229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41934835-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KAT6A | NM_006766.5 | c.3385C>T | p.Arg1129Ter | stop_gained | 17/17 | ENST00000265713.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KAT6A | ENST00000265713.8 | c.3385C>T | p.Arg1129Ter | stop_gained | 17/17 | 1 | NM_006766.5 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 34
GnomAD4 exome
Cov.:
34
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:15
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome Pathogenic:6
Pathogenic, criteria provided, single submitter | research | Duke University Health System Sequencing Clinic, Duke University Health System | Apr 20, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 14, 2022 | - - |
Pathogenic, criteria provided, single submitter | research | DECIPHERD-UDD, Universidad del Desarrollo | Jul 01, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Daryl Scott Lab, Baylor College of Medicine | Nov 10, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Oct 19, 2020 | Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0204 - Variant is predicted to result in a truncated protein with more than 1/3 of the protein affected (exon 17 of 17). (P) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0401 - Variant is located in a gene associated with a severe early-onset dominant condition that is intolerant to loss-of-function variants. (P) 0601 - Variant affects at least one well-established (essential) functional domain or motif. The variant is located within the transactivation domain which is essential for normal protein function (PMID: 25728777). (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Many other downstream truncating variants have previously been reported as pathogenic (ClinVar, PMID: 30245513). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported as de novo in multiple patients (ClinVar, PMID: 25728775, PMID: 30245513). (P) 1203 - Variant shown to be de novo in proband (parental status confirmed). (P) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 05, 2015 | - - |
not provided Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 07, 2022 | This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 180229). This premature translational stop signal has been observed in individual(s) with KAT6A-related conditions (PMID: 25728775, 32041641). In at least one individual the variant was observed to be de novo. This sequence change creates a premature translational stop signal (p.Arg1129*) in the KAT6A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 876 amino acid(s) of the KAT6A protein. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Apr 06, 2022 | PVS1, PM2_SUP, PS3 - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2019 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratoire de Génétique Moléculaire, CHU Bordeaux | - | - - |
KAT6A syndrome Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | UCLA Clinical Genomics Center, UCLA | Jan 15, 2015 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille | Jan 01, 2019 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 28, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
D
MutationTaster
Benign
D;D;D
Vest4
0.97
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at