11-65712276-G-C

Position:

• chr11-65712276-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 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 -5 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KAT5. . Gene score misZ 3.6126 (greater than the threshold 3.09). Trascript score misZ 3.7394 (greater than threshold 3.09). GenCC has associacion of gene with neurodevelopmental disorder with dysmorphic facies, sleep disturbance, and brain abnormalities.
• 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

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
MutationTaster	Benign	0.87	N;N;N;N
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;