rs199470480

Variant names:

• chr10-75029723-AAGTGCCATCTC-A
• rs199470480
• NM_012330.4:c.4911_4921delAGTGCCATCTC

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.4911_4921delAGTGCCATCTC​(p.Val1638AlafsTer27) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KAT6B NM_012330.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 7.67

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 16 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-75029723-AAGTGCCATCTC-A is Pathogenic according to our data. Variant chr10-75029723-AAGTGCCATCTC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 140476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-75029723-AAGTGCCATCTC-A is described in Lovd as [Likely_pathogenic]. Variant chr10-75029723-AAGTGCCATCTC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KAT6B	NM_012330.4	c.4911_4921delAGTGCCATCTC	p.Val1638AlafsTer27	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.4911_4921delAGTGCCATCTC	p.Val1638AlafsTer27	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/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 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

- -

Dec 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 11, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in abnormal protein length as the last 436 amino acids are replaced with 26 different amino acids, and other similar variants have been reported in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22077973, 35991575, Daniels2023[Poster], 25424711) -

Blepharophimosis - intellectual disability syndrome, SBBYS type Pathogenic:2

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Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PVS1_Strong+PM6_Supporting+PP4 -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199470480; hg19: chr10-76789481;