rs199470470

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KAT6B NM_012330.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 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
• RASopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 18 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 83 pathogenic variants in the truncated region.
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KAT6B	NM_012330.4	c.3769_3772delTCTA	p.Lys1258GlyfsTer13	frameshift_variant	Exon 18 of 18	ENST00000287239.10	NP_036462.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KAT6B	ENST00000287239.10	c.3769_3772delTCTA	p.Lys1258GlyfsTer13	frameshift_variant	Exon 18 of 18	1	NM_012330.4	ENSP00000287239.4

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

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Genitopatellar syndrome Pathogenic:4 Other:1

Jun 03, 2019

Department of Medical Genetics, Oslo University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 10, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

May 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Lys1258Glyfs*13) in the KAT6B gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 816 amino acid(s) of the KAT6B protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with genitopatellar syndrome (PMID: 12949978, 22265014, 25424711). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 30530). For these reasons, this variant has been classified as Pathogenic. -

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Jun 13, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3769_3772delTCTA (p.K1258Gfs*13) alteration, located in exon 18 (coding exon 16) of the KAT6B gene, consists of a deletion of 4 nucleotides from position 3769 to 3772, causing a translational frameshift with a predicted alternate stop codon after 13 amino acids. This alteration occurs at the 3' terminus of the KAT6B gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 39.3% of the protein. Premature stop codons are typically deleterious in nature. Furthermore, the impacted region is critical for protein function and a significant portion of the protein is affected (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported in multiple individuals with features consistent with genitopatellar syndrome, including multiple cases of reported de novo occurrence (Simpson, 2012; Campeau, 2012; Gannon, 2015; Takahashi, 2020; Zhang, 2020; Tønne, 2021; Yabumoto, 2021). 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). Based on the available evidence, this alteration is classified as pathogenic. -

not provided Other:1

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Lee Lab(KAT6B), Baylor College of Medicine

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

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;