chr8-41933268-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1651S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 3 hom. )

Consequence

KAT6A
NM_006766.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.516

Publications

8 publications found

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]

KAT6A Gene-Disease associations (from GenCC):

autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Illumina
syndromic intellectual disability
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

KAT6A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 445624.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 206 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006766.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KAT6A	NM_006766.5	MANE Select	c.4952C>T	p.Pro1651Leu	missense	Exon 17 of 17	NP_006757.2	Q92794

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KAT6A	ENST00000265713.8	TSL:1 MANE Select	c.4952C>T	p.Pro1651Leu	missense	Exon 17 of 17	ENSP00000265713.2	Q92794
KAT6A	ENST00000406337.6	TSL:5	c.4958C>T	p.Pro1653Leu	missense	Exon 18 of 18	ENSP00000385888.2	A0A3F2YNX6
KAT6A	ENST00000396930.4	TSL:5	c.4952C>T	p.Pro1651Leu	missense	Exon 18 of 18	ENSP00000380136.3	Q92794

Frequencies

GnomAD3 genomes

AF:

0.00136

AC:

206

AN:

151584

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.00124

AC:

229

AN:

183942

AF XY:

0.00114

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 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.:

Cov.:

AF XY:

0.00169

AC XY:

1180

AN XY:

699934

show subpopulations

African (AFR)

AF:

0.000548

AC:

AN:

32854

American (AMR)

AF:

0.000585

AC:

AN:

41014

Ashkenazi Jewish (ASJ)

AF:

0.000779

AC:

AN:

24376

East Asian (EAS)

AF:

0.00

AC:

AN:

38212

South Asian (SAS)

AF:

0.0000248

AC:

AN:

80494

European-Finnish (FIN)

AF:

0.00182

AC:

AN:

38912

Middle Eastern (MID)

AF:

0.000579

AC:

AN:

5178

European-Non Finnish (NFE)

AF:

0.00210

AC:

2295

AN:

1093720

Other (OTH)

AF:

0.00124

AC:

AN:

58798

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

158

315

473

630

788

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

188

282

376

470

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00136

AC:

206

AN:

151696

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

AN XY:

74152

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41474

American (AMR)

AF:

0.00203

AC:

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.000578

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00160

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00211

AC:

143

AN:

67658

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00202

Hom.:

Bravo

AF:

0.00155

ESP6500AA

AF:

0.000471

AC:

ESP6500EA

AF:

0.00171

AC:

ExAC

AF:

0.000852

AC:

102

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

Autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome (1)

Inborn genetic diseases (1)

KAT6A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.11

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.45

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.59

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.81

PhyloP100

0.52

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.4

REVEL

Benign

0.035

Sift

Uncertain

0.0060

Sift4G

Benign

0.075

Polyphen

0.10

Vest4

0.39

MVP

0.29

MPC

0.19

ClinPred

0.010

GERP RS

3.5

Varity_R

0.070

gMVP

0.11

Mutation Taster

=94/6

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over