rs144417514

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_006766.5(KAT6A):​c.4952C>T​(p.Pro1651Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 1,565,254 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0018 ( 3 hom. )

Consequence

KAT6A
NM_006766.5 missense

Scores

4
15

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.516
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0101650655).
BP6
Variant 8-41933268-G-A is Benign according to our data. Variant chr8-41933268-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 445624.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-41933268-G-A is described in Lovd as [Likely_benign].
BS2
High AC in GnomAd4 at 206 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KAT6ANM_006766.5 linkc.4952C>T p.Pro1651Leu missense_variant 17/17 ENST00000265713.8 NP_006757.2 Q92794A5PKX7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KAT6AENST00000265713.8 linkc.4952C>T p.Pro1651Leu missense_variant 17/171 NM_006766.5 ENSP00000265713.2 Q92794

Frequencies

GnomAD3 genomes
AF:
0.00136
AC:
206
AN:
151584
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000266
Gnomad AMI
AF:
0.00110
Gnomad AMR
AF:
0.00204
Gnomad ASJ
AF:
0.000578
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00160
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00211
Gnomad OTH
AF:
0.000483
GnomAD3 exomes
AF:
0.00124
AC:
229
AN:
183942
Hom.:
0
AF XY:
0.00114
AC XY:
113
AN XY:
98968
show subpopulations
Gnomad AFR exome
AF:
0.000326
Gnomad AMR exome
AF:
0.000439
Gnomad ASJ exome
AF:
0.000941
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00205
Gnomad NFE exome
AF:
0.00223
Gnomad OTH exome
AF:
0.000616
GnomAD4 exome
AF:
0.00177
AC:
2505
AN:
1413558
Hom.:
3
Cov.:
36
AF XY:
0.00169
AC XY:
1180
AN XY:
699934
show subpopulations
Gnomad4 AFR exome
AF:
0.000548
Gnomad4 AMR exome
AF:
0.000585
Gnomad4 ASJ exome
AF:
0.000779
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000248
Gnomad4 FIN exome
AF:
0.00182
Gnomad4 NFE exome
AF:
0.00210
Gnomad4 OTH exome
AF:
0.00124
GnomAD4 genome
AF:
0.00136
AC:
206
AN:
151696
Hom.:
0
Cov.:
32
AF XY:
0.00120
AC XY:
89
AN XY:
74152
show subpopulations
Gnomad4 AFR
AF:
0.000265
Gnomad4 AMR
AF:
0.00203
Gnomad4 ASJ
AF:
0.000578
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00160
Gnomad4 NFE
AF:
0.00211
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.00190
Hom.:
0
Bravo
AF:
0.00155
ESP6500AA
AF:
0.000471
AC:
2
ESP6500EA
AF:
0.00171
AC:
14
ExAC
AF:
0.000852
AC:
102

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:7
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 30, 2024- -
Likely benign, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsFeb 20, 2017- -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2024KAT6A: BS1 -
Benign, criteria provided, single submitterclinical testingGeneDxDec 17, 2018- -
KAT6A-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesApr 29, 2019This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsFeb 07, 2018This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.41
T
BayesDel_noAF
Benign
-0.37
CADD
Benign
12
DANN
Benign
0.69
DEOGEN2
Benign
0.11
.;T;T;.
Eigen
Benign
-0.52
Eigen_PC
Benign
-0.45
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Benign
0.59
T;.;T;T
M_CAP
Uncertain
0.12
D
MetaRNN
Benign
0.010
T;T;T;T
MetaSVM
Benign
-0.88
T
MutationAssessor
Benign
0.81
.;L;L;.
PrimateAI
Uncertain
0.62
T
PROVEAN
Benign
-1.4
N;N;N;.
REVEL
Benign
0.035
Sift
Uncertain
0.0060
D;D;D;.
Sift4G
Benign
0.075
.;T;T;.
Polyphen
0.10
.;B;B;.
Vest4
0.39, 0.36
MVP
0.29
MPC
0.19
ClinPred
0.010
T
GERP RS
3.5
Varity_R
0.070
gMVP
0.11

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs144417514; hg19: chr8-41790786; API