17-42113777-C-T

Variant names:

• chr17-42113777-C-T
• rs1555665209
• NM_021078.3:c.2386G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_021078.3(KAT2A):​c.2386G>A​(p.Asp796Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D796Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KAT2A NM_021078.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021078.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KAT2A	NM_021078.3	MANE Select	c.2386G>A	p.Asp796Asn	missense	Exon 18 of 18	NP_066564.2	Q92830-1
	KAT2A	NM_001376227.1		c.2389G>A	p.Asp797Asn	missense	Exon 18 of 18	NP_001363156.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KAT2A	ENST00000225916.10	TSL:1 MANE Select	c.2386G>A	p.Asp796Asn	missense	Exon 18 of 18	ENSP00000225916.5	Q92830-1
	KAT2A	ENST00000873177.1		c.2407G>A	p.Asp803Asn	missense	Exon 18 of 18	ENSP00000543236.1
	KAT2A	ENST00000873169.1		c.2398G>A	p.Asp800Asn	missense	Exon 18 of 18	ENSP00000543228.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000405 AC: 1 AN: 246712 AF XY: 0.00000748

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000472

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457812 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725396

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33130

American (AMR) AF: 0.00 AC: 0 AN: 43662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26020

East Asian (EAS) AF: 0.00 AC: 0 AN: 39532

South Asian (SAS) AF: 0.00 AC: 0 AN: 85912

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52984

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110630

Other (OTH) AF: 0.00 AC: 0 AN: 60224

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	-0.0046	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		7.9
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.84		Gain of MoRF binding (P = 0.0462)
MVP		0.84
MPC		2.1
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.88
gMVP		0.89

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

Other links and lift over

dbSNP: rs1555665209; hg19: chr17-40265795;