NM_012330.4:c.3769_3772delTCTA

Variant names:

• chr10-75028588-GTCTA-G
• rs199470470
• NM_012330.4:c.3769_3772delTCTA

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_012330.4(KAT6B):​c.3769_3772delTCTA​(p.Lys1258GlyfsTer13) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001444330: Functional studies of fibroblast cells from a patient with a heterozygous p.L1258Gfs*13 alteration showed a mature, but truncated KAT6B protein product. Additional studies showed a significant reduction in histone (H3 and H4) acetylation in patient fibroblasts compared to control samples, suggesting the truncated protein results in altered protein activity (Simpson, 2012).".

• Frequency: Genomes: not found (cov: 32)
• Consequence: KAT6B NM_012330.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:2
• Conservation: PhyloP100: 5.34
• Publications: 6 publications found

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]

KAT6B Gene-Disease associations (from GenCC):

• blepharophimosis - intellectual disability syndrome, SBBYS type

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• genitopatellar syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• KAT6B-related multiple congenital anomalies syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• multiple congenital anomalies/dysmorphic syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• RASopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 22 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 85 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV001444330: Functional studies of fibroblast cells from a patient with a heterozygous p.L1258Gfs*13 alteration showed a mature, but truncated KAT6B protein product. Additional studies showed a significant reduction in histone (H3 and H4) acetylation in patient fibroblasts compared to control samples, suggesting the truncated protein results in altered protein activity (Simpson, 2012).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-75028588-GTCTA-G is Pathogenic according to our data. Variant chr10-75028588-GTCTA-G is described in ClinVar as Pathogenic. ClinVar VariationId is 30530.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012330.4. 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
	KAT6B	NM_012330.4	MANE Select	c.3769_3772delTCTA	p.Lys1258GlyfsTer13	frameshift	Exon 18 of 18	NP_036462.2	Q8WYB5-1
	KAT6B	NM_001370136.1		c.3769_3772delTCTA	p.Lys1258GlyfsTer13	frameshift	Exon 18 of 18	NP_001357065.1	Q8WYB5-1
	KAT6B	NM_001370137.1		c.3769_3772delTCTA	p.Lys1258GlyfsTer13	frameshift	Exon 18 of 18	NP_001357066.1	Q8WYB5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KAT6B	ENST00000287239.10	TSL:1 MANE Select	c.3769_3772delTCTA	p.Lys1258GlyfsTer13	frameshift	Exon 18 of 18	ENSP00000287239.4	Q8WYB5-1
	KAT6B	ENST00000372711.2	TSL:1	c.3220_3223delTCTA	p.Lys1075GlyfsTer13	frameshift	Exon 18 of 18	ENSP00000361796.1	Q8WYB5-2
	KAT6B	ENST00000648725.1		c.3769_3772delTCTA	p.Lys1258GlyfsTer13	frameshift	Exon 18 of 18	ENSP00000497841.1	Q8WYB5-1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Genitopatellar syndrome (5)
1	-	-	Inborn genetic diseases (1)
1	-	-	KAT6B-Related Spectrum Disorders (1)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.3
Mutation Taster		=3/197	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs199470470; hg19: chr10-76788346;