11-65712276-G-C

Position:

• chr11-65712276-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_182710.3(KAT5):​c.9G>C​(p.Glu3Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,273,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: KAT5 NM_182710.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.21

Genes affected

KAT5 (HGNC:5275): (lysine acetyltransferase 5) The protein encoded by this gene belongs to the MYST family of histone acetyl transferases (HATs) and was originally isolated as an HIV-1 TAT-interactive protein. HATs play important roles in regulating chromatin remodeling, transcription and other nuclear processes by acetylating histone and nonhistone proteins. This protein is a histone acetylase that has a role in DNA repair and apoptosis and is thought to play an important role in signal transduction. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14616829).
• BS2: High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KAT5	NM_182710.3	c.9G>C	p.Glu3Asp	missense_variant	1/13	ENST00000341318.9	NP_874369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KAT5	ENST00000341318.9	c.9G>C	p.Glu3Asp	missense_variant	1/13	1	NM_182710.3	ENSP00000340330.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000118 AC: 15 AN: 1273134 Hom.: 0 Cov.: 31 AF XY: 0.0000130 AC XY: 8 AN XY: 617312

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000238

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000191

GnomAD4 genome Cov.: 31

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodevelopmental disorder with dysmorphic facies, sleep disturbance, and brain abnormalities Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

May 20, 2023

The observed missense c.9G>C(p.Glu3Asp) variant in KAT5 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is absent in gnomAD Exomes. The amino acid Glu at position 3 is changed to a Asp changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Glu3Asp in KAT5 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Computational evidence (Polyphen - Possibly Damaging/Benign, SIFT - Damaging, and MutationTaster - Disease causing) predicts conflicting evidence on protein structure and function for this variant. For these reasons, this variant has been classified as Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T;.;.;.
Eigen	Benign	0.070
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.69	T;T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.15	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;L;L;L
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.080	N;N;N;N
REVEL	Benign	0.073
Sift	Benign	0.34	T;T;D;D
Sift4G	Benign	0.42	T;T;D;T
Polyphen		0.066	B;P;P;.
Vest4		0.10
MutPred		0.18		Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);
MVP		0.60
MPC		0.82
ClinPred		0.72	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.47
gMVP		0.77

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

Other links and lift over

dbSNP: rs952759552; hg19: chr11-65479747; COSMIC: COSV58063444; COSMIC: COSV58063444;