16-31120243-A-G

Position:

• chr16-31120243-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_032188.3(KAT8):​c.269A>G​(p.Tyr90Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KAT8 NM_032188.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.37

Genes affected

KAT8 (HGNC:17933): (lysine acetyltransferase 8) This gene encodes a member of the MYST histone acetylase protein family. The encoded protein has a characteristic MYST domain containing an acetyl-CoA-binding site, a chromodomain typical of proteins which bind histones, and a C2HC-type zinc finger. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2012]

KAT8 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.923
• PP5: Variant 16-31120243-A-G is Pathogenic according to our data. Variant chr16-31120243-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 976460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KAT8	NM_032188.3	c.269A>G	p.Tyr90Cys	missense_variant	2/11	ENST00000219797.9	NP_115564.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KAT8	ENST00000219797.9	c.269A>G	p.Tyr90Cys	missense_variant	2/11	1	NM_032188.3	ENSP00000219797.3
KAT8	ENST00000448516.6	c.269A>G	p.Tyr90Cys	missense_variant	2/10	1		ENSP00000406037.2
KAT8	ENST00000543774.6	c.269A>G	p.Tyr90Cys	missense_variant	3/12	5		ENSP00000456933.2
KAT8	ENST00000539683.2	n.254A>G		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Li-Ghorbani-Weisz-Hubshman syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PS3+PS4_Supporting+PP4+PM6 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 12, 2020	- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.269A>G (p.Y90C) alteration is located in exon 2 (coding exon 2) of the KAT8 gene. This alteration results from an A to G substitution at nucleotide position 269, causing the tyrosine (Y) at amino acid position 90 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported de novo in three unrelated patients with a neurodevelopmental disorder (Li, 2020). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D;.;D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	.;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Uncertain	0.10	D
MutationAssessor	Pathogenic	3.8	H;H;H
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-8.6	.;D;D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	.;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.89
MutPred		0.76		Loss of phosphorylation at Y90 (P = 0.0817);Loss of phosphorylation at Y90 (P = 0.0817);Loss of phosphorylation at Y90 (P = 0.0817);
MVP		0.89
MPC		2.5
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.96

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: rs2057483219; hg19: chr16-31131564; COSMIC: COSV54898644; COSMIC: COSV54898644;