rs199470484

Positions:

• chr10-75030213-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_012330.4(KAT6B):​c.5389C>T​(p.Arg1797Ter) variant causes a stop gained change involving the alteration of a non-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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KAT6B NM_012330.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:2
• Conservation: PhyloP100: 2.63

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-75030213-C-T is Pathogenic according to our data. Variant chr10-75030213-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 50357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-75030213-C-T is described in Lovd as [Likely_pathogenic]. Variant chr10-75030213-C-T is described in Lovd as [Pathogenic]. Variant chr10-75030213-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KAT6B	NM_012330.4	c.5389C>T	p.Arg1797Ter	stop_gained	18/18	ENST00000287239.10	NP_036462.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KAT6B	ENST00000287239.10	c.5389C>T	p.Arg1797Ter	stop_gained	18/18	1	NM_012330.4	ENSP00000287239	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:2

Revision: criteria provided, single submitter

Submissions by phenotype

Blepharophimosis - intellectual disability syndrome, SBBYS type Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2013	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Genitopatellar syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 26, 2020

For these reasons, this variant has been classified as Pathogenic. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has been observed in individual(s) with Say-Barber-Biesecker-Young-Simpson syndrome (PMID: 22077973, 23436491). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 50357). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the KAT6B gene (p.Arg1797*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 277 amino acids of the KAT6B protein. -

not provided Other:1

not provided, no classification provided

literature only

Lee Lab(KAT6B), Baylor College of Medicine

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.84	D
MutationTaster	Benign	1.0	D;D;D;D;D
Vest4		0.87, 0.91, 0.91, 0.89
GERP RS		5.5

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: rs199470484; hg19: chr10-76789971; COSMIC: COSV54751807; COSMIC: COSV54751807;