10-75030213-C-T

Variant names:

• chr10-75030213-C-T
• rs199470484
• NM_012330.4:c.5389C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_012330.4(KAT6B):​c.5389C>T​(p.Arg1797*) 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, multiple submitters, no conflicts P:4 O:2
• Conservation: PhyloP100: 2.63
• 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
• RASopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 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 11 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 VariationId is 50357.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KAT6B	NM_012330.4	MANE Select	c.5389C>T	p.Arg1797*	stop_gained	Exon 18 of 18	NP_036462.2
	KAT6B	NM_001370136.1		c.5389C>T	p.Arg1797*	stop_gained	Exon 18 of 18	NP_001357065.1
	KAT6B	NM_001370137.1		c.5389C>T	p.Arg1797*	stop_gained	Exon 18 of 18	NP_001357066.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KAT6B	ENST00000287239.10	TSL:1 MANE Select	c.5389C>T	p.Arg1797*	stop_gained	Exon 18 of 18	ENSP00000287239.4
	KAT6B	ENST00000372711.2	TSL:1	c.4840C>T	p.Arg1614*	stop_gained	Exon 18 of 18	ENSP00000361796.1
	KAT6B	ENST00000648725.1		c.5389C>T	p.Arg1797*	stop_gained	Exon 18 of 18	ENSP00000497841.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Blepharophimosis - intellectual disability syndrome, SBBYS type Pathogenic:2 Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Apr 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Nov 05, 2024

Gharavi Laboratory, Columbia University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: case-control

Genitopatellar syndrome Pathogenic:1

Apr 26, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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).

KAT6B-related multiple congenital anomalies syndrome Pathogenic:1

Oct 09, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are likely mechanisms of disease in this gene and are associated with Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) (MIM#603736) and genitopatellar syndrome (GPS) (MIM#606170), respectively; these two conditions are also referred to as KAT6B-related multiple congenital anomalies syndrome (MONDO:0036042) which also include individuals with intermediate phenotypes consisting of SBBYSS and GPS features. NMD-predicted variants have a loss of function mechanism, and are associated with SBBYSS. Truncating variants (PTVs) found in the last exon have been reported for both conditions, and are likely to have both a loss- and gain of function effect. PTVs found in the proximal end of the final exon have been reported in patients with GPS, while PTVs in the terminal end of the final exon have SBBYSS (PMIDs: 22715153, 32424177). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0701 - Other protein truncating variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. More than five downstream truncating variants have been identified in individuals with SSBYSS or with an intermediate phenotype overlapping both SBBYSS and GPS (PMID: 32424177). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as de novo in at least three individuals with SBBYSS or an intermediate phenotype with overlapping features of SBBYSS and GPS (PMIDs: 22077973, 23436491, 28857140). It has also been classified as pathogenic by a clinical laboratory in ClinVar. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

not provided Other:1

Lee Lab(KAT6B), Baylor College of Medicine

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		2.6
Vest4		0.87
GERP RS		5.5
Mutation Taster		=1/199	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: rs199470484; hg19: chr10-76789971; COSMIC: COSV54751807; COSMIC: COSV54751807;