8-41932216-T-C

Position:

chr8-41932216-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4BP6_Very_StrongBS2

The NM_006766.5(KAT6A):c.6004A>G(p.Met2002Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000284 in 1,585,136 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 1 hom. )

Consequence

KAT6A
NM_006766.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 7.52

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KAT6A. . Gene score misZ 2.0718 (greater than the threshold 3.09). Trascript score misZ 3.1208 (greater than threshold 3.09). GenCC has associacion of gene with syndromic intellectual disability, autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.34736007).

BP6

Variant 8-41932216-T-C is Benign according to our data. Variant chr8-41932216-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1991189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KAT6A	NM_006766.5 linkuse as main transcript	c.6004A>G	p.Met2002Val	missense_variant	17/17	ENST00000265713.8	NP_006757.2	Q92794A5PKX7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KAT6A	ENST00000265713.8 linkuse as main transcript	c.6004A>G	p.Met2002Val	missense_variant	17/17	1	NM_006766.5	ENSP00000265713.2	Q92794
KAT6A	ENST00000406337.6 linkuse as main transcript	c.6010A>G	p.Met2004Val	missense_variant	18/18	5		ENSP00000385888.2	A0A3F2YNX6
KAT6A	ENST00000396930.4 linkuse as main transcript	c.6004A>G	p.Met2002Val	missense_variant	18/18	5		ENSP00000380136.3	Q92794
KAT6A	ENST00000649817.1 linkuse as main transcript	c.4684A>G	p.Met1562Val	missense_variant	11/11			ENSP00000497780.1	A0A3B3ITI3

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000384

AC:

AN:

234300

Hom.:

AF XY:

0.0000474

AC XY:

AN XY:

126592

show subpopulations

Gnomad AFR exome

AF:

0.0000624

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000561

Gnomad SAS exome

AF:

0.000221

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000929

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000272

AC:

AN:

1432926

Hom.:

Cov.:

AF XY:

0.0000366

AC XY:

AN XY:

709982

show subpopulations

Gnomad4 AFR exome

AF:

0.000123

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.000172

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000146

Gnomad4 OTH exome

AF:

0.0000508

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000247

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

KAT6A-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 04, 2023

This 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). -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 27, 2022

This 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. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 09, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.031

BayesDel_noAF

Uncertain

0.010

CADD

Benign

DANN

Benign

0.70

DEOGEN2

Uncertain

0.42

.;T;T

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.89

D;.;D

M_CAP

Benign

0.026

MetaRNN

Benign

0.35

T;T;T

MetaSVM

Benign

-0.49

MutationAssessor

Benign

0.81

.;L;L

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-2.7

.;D;D

REVEL

Uncertain

0.31

Sift

Uncertain

0.0020

.;D;D

Sift4G

Uncertain

0.0030

.;D;D

Polyphen

0.97

.;D;D

Vest4

0.77, 0.80

MutPred

0.23

.;Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);

MVP

0.78

MPC

0.19

ClinPred

0.18

GERP RS

5.8

Varity_R

0.61

gMVP

0.62

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over