Genetic Variant KAT2A:p.Thr570Ser (chr17-42117090-G-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_021078.3(KAT2A):c.1709C>G(p.Thr570Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00026 in 1,614,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 0 hom. )

Consequence

KAT2A
NM_021078.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 10.0

Variant links:

Genes affected

KAT2A (HGNC:4201): (lysine acetyltransferase 2A) KAT2A, or GCN5, is a histone acetyltransferase (HAT) that functions primarily as a transcriptional activator. It also functions as a repressor of NF-kappa-B (see MIM 164011) by promoting ubiquitination of the NF-kappa-B subunit RELA (MIM 164014) in a HAT-independent manner (Mao et al., 2009 [PubMed 19339690]).[supplied by OMIM, Sep 2009]

KAT2A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1126464).

BS2

High AC in GnomAd4 at 35 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KAT2A	NM_021078.3 link	c.1709C>G	p.Thr570Ser	missense_variant	Exon 11 of 18	ENST00000225916.10	NP_066564.2	Q92830-1
KAT2A	NM_001376227.1 link	c.1709C>G	p.Thr570Ser	missense_variant	Exon 11 of 18		NP_001363156.1
KAT2A	XM_006721818.5 link	c.626C>G	p.Thr209Ser	missense_variant	Exon 6 of 13		XP_006721881.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KAT2A	ENST00000225916.10 link	c.1709C>G	p.Thr570Ser	missense_variant	Exon 11 of 18	1	NM_021078.3	ENSP00000225916.5	Q92830-1
KAT2A	ENST00000465682.5 link	n.*823C>G		non_coding_transcript_exon_variant	Exon 11 of 18	5		ENSP00000468390.1	K7ERS6
KAT2A	ENST00000592310.1 link	n.400C>G		non_coding_transcript_exon_variant	Exon 1 of 2	3
KAT2A	ENST00000465682.5 link	n.*823C>G		3_prime_UTR_variant	Exon 11 of 18	5		ENSP00000468390.1	K7ERS6

Frequencies

GnomAD3 genomes

AF:

0.000230

AC:

AN:

152262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000219

AC:

AN:

251352

Hom.:

AF XY:

0.000236

AC XY:

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000449

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000263

AC:

384

AN:

1461818

Hom.:

Cov.:

AF XY:

0.000253

AC XY:

184

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000328

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000230

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000223

Hom.:

Bravo

AF:

0.000215

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000338

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 10, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1709C>G (p.T570S) alteration is located in exon 11 (coding exon 11) of the KAT2A gene. This alteration results from a C to G substitution at nucleotide position 1709, causing the threonine (T) at amino acid position 570 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

DANN

Benign

0.95

DEOGEN2

Benign

0.18

Eigen

Benign

-0.22

Eigen_PC

Benign

0.012

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.74

M_CAP

Benign

0.011

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.080

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.76

REVEL

Uncertain

0.34

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.39

MutPred

0.29

Gain of sheet (P = 0.1539);

MVP

0.29

MPC

0.85

ClinPred

0.18

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.67

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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