3-20040581-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_003884.5(KAT2B):c.104C>T(p.Ala35Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000191 in 1,163,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00092 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000086 (0 hom.)
• Consequence: KAT2B NM_003884.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.465

Genes affected

KAT2B (HGNC:8638): (lysine acetyltransferase 2B) CBP and p300 are large nuclear proteins that bind to many sequence-specific factors involved in cell growth and/or differentiation, including c-jun and the adenoviral oncoprotein E1A. The protein encoded by this gene associates with p300/CBP. It has in vitro and in vivo binding activity with CBP and p300, and competes with E1A for binding sites in p300/CBP. It has histone acetyl transferase activity with core histones and nucleosome core particles, indicating that this protein plays a direct role in transcriptional regulation. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.029607385).
• BP6: Variant 3-20040581-C-T is Benign according to our data. Variant chr3-20040581-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2378894.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd at 135 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KAT2B	NM_003884.5	c.104C>T	p.Ala35Val	missense_variant	1/18	ENST00000263754.5
KAT2B	XM_005265528.5	c.104C>T	p.Ala35Val	missense_variant	1/17
KAT2B	XM_047449147.1	c.-392C>T		5_prime_UTR_variant	1/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KAT2B	ENST00000263754.5	c.104C>T	p.Ala35Val	missense_variant	1/18	1	NM_003884.5	P1

Frequencies

GnomAD3 genomes AF: 0.000916 AC: 135 AN: 147358 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00323

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000673

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000988

GnomAD4 exome AF: 0.0000857 AC: 87 AN: 1015700 Hom.: 0 Cov.: 31 AF XY: 0.0000793 AC XY: 38 AN XY: 478952

Gnomad4 AFR exome AF: 0.00383

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: 0.00000342

Gnomad4 OTH exome AF: 0.000103

GnomAD4 genome AF: 0.000915 AC: 135 AN: 147470 Hom.: 0 Cov.: 31 AF XY: 0.000904 AC XY: 65 AN XY: 71872

Gnomad4 AFR AF: 0.00322

Gnomad4 AMR AF: 0.0000673

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000978

Alfa AF: 0.000569 Hom.: 0

Bravo AF: 0.000922

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 09, 2022

The c.104C>T (p.A35V) alteration is located in exon 1 (coding exon 1) of the KAT2B gene. This alteration results from a C to T substitution at nucleotide position 104, causing the alanine (A) at amino acid position 35 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

KAT2B-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 14, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.030	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.81	N
REVEL	Benign	0.052
Sift	Benign	0.064	T
Sift4G	Benign	0.091	T
Polyphen		0.015	B
Vest4		0.14
MutPred		0.12		Loss of glycosylation at P33 (P = 0.0691);
MVP		0.12
MPC		1.8
ClinPred		0.11	T
GERP RS		0.94
Varity_R		0.058
gMVP		0.15

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: rs995249037; hg19: chr3-20082073;