17-42117690-C-T

Variant names:

• chr17-42117690-C-T
• rs948140872
• NM_021078.3:c.1416G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_021078.3(KAT2A):​c.1416G>A​(p.Met472Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,298 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KAT2A NM_021078.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KAT2A	NM_021078.3	c.1416G>A	p.Met472Ile	missense_variant	Exon 9 of 18	ENST00000225916.10	NP_066564.2
KAT2A	NM_001376227.1	c.1416G>A	p.Met472Ile	missense_variant	Exon 9 of 18		NP_001363156.1
KAT2A	XM_006721818.5	c.333G>A	p.Met111Ile	missense_variant	Exon 4 of 13		XP_006721881.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KAT2A	ENST00000225916.10	c.1416G>A	p.Met472Ile	missense_variant	Exon 9 of 18	1	NM_021078.3	ENSP00000225916.5
KAT2A	ENST00000465682.5	n.*530G>A		non_coding_transcript_exon_variant	Exon 9 of 18	5		ENSP00000468390.1
KAT2A	ENST00000465682.5	n.*530G>A		3_prime_UTR_variant	Exon 9 of 18	5		ENSP00000468390.1
KAT2A	ENST00000592310.1	n.-201G>A		upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458298 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 724914

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1416G>A (p.M472I) alteration is located in exon 9 (coding exon 9) of the KAT2A gene. This alteration results from a G to A substitution at nucleotide position 1416, causing the methionine (M) at amino acid position 472 to be replaced by an isoleucine (I). 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	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.26
Sift	Benign	0.057	T
Sift4G	Benign	0.13	T
Polyphen		0.048	B
Vest4		0.67
MutPred		0.30		Loss of disorder (P = 0.0568);
MVP		0.46
MPC		1.1
ClinPred		0.94	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.52
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs948140872; hg19: chr17-40269708;