10-75028731-A-G

Position:

• chr10-75028731-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM2 PP2 BP4_Strong BP6_Moderate

The NM_012330.4(KAT6B):​c.3907A>G​(p.Ser1303Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KAT6B NM_012330.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.196

Genes affected

KAT6B (HGNC:17582): (lysine acetyltransferase 6B) The protein encoded by this gene is a histone acetyltransferase and component of the MOZ/MORF protein complex. In addition to its acetyltransferase activity, the encoded protein has transcriptional activation activity in its N-terminal end and transcriptional repression activity in its C-terminal end. This protein is necessary for RUNX2-dependent transcriptional activation and could be involved in brain development. Mutations have been found in patients with genitopatellar syndrome. A translocation of this gene and the CREBBP gene results in acute myeloid leukemias. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KAT6B. . Gene score misZ 2.8874 (greater than the threshold 3.09). Trascript score misZ 4.8748 (greater than threshold 3.09). GenCC has associacion of gene with RASopathy, genitopatellar syndrome, KAT6B-related multiple congenital anomalies syndrome, blepharophimosis - intellectual disability syndrome, SBBYS type.
• BP4: Computational evidence support a benign effect (MetaRNN=0.04773566).
• BP6: Variant 10-75028731-A-G is Benign according to our data. Variant chr10-75028731-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 376923.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KAT6B	NM_012330.4	c.3907A>G	p.Ser1303Gly	missense_variant	18/18	ENST00000287239.10	NP_036462.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KAT6B	ENST00000287239.10	c.3907A>G	p.Ser1303Gly	missense_variant	18/18	1	NM_012330.4	ENSP00000287239.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461746 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727190

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Jan 25, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	7.4
DANN	Benign	0.72
DEOGEN2	Benign	0.13	T;.;T;.;.;.;.;.;.;T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.030	N
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.048	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N;.;N;.;.;.;.;.;.;N;.;.
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.2	.;.;.;N;.;.;.;.;N;N;.;N
REVEL	Benign	0.15
Sift	Uncertain	0.014	.;.;.;D;.;.;.;.;D;D;.;D
Sift4G	Benign	0.19	.;.;.;T;.;.;.;.;T;T;.;T
Polyphen		0.0020	B;B;B;B;.;.;B;B;B;B;.;B
Vest4		0.064, 0.089, 0.051, 0.036
MutPred		0.17		Loss of phosphorylation at S1303 (P = 0.0025);.;Loss of phosphorylation at S1303 (P = 0.0025);.;.;.;.;.;.;Loss of phosphorylation at S1303 (P = 0.0025);Loss of phosphorylation at S1303 (P = 0.0025);.;
MVP		0.27
MPC		0.18
ClinPred		0.028	T
GERP RS		-3.6
Varity_R		0.045
gMVP		0.031

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: rs1057520090; hg19: chr10-76788489;