rs1554846212

Variant names:

• chr10-75030037-C-T
• rs1554846212
• NM_012330.4:c.5213C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_012330.4(KAT6B):​c.5213C>T​(p.Thr1738Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1738T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KAT6B NM_012330.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 0.610
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-75030037-C-T is Pathogenic according to our data. Variant chr10-75030037-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 523500.
• BP4: Computational evidence support a benign effect (MetaRNN=0.13980931). . Strength limited to SUPPORTING due to the PP5.

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.5213C>T	p.Thr1738Ile	missense	Exon 18 of 18	NP_036462.2	Q8WYB5-1
	KAT6B	NM_001370136.1		c.5213C>T	p.Thr1738Ile	missense	Exon 18 of 18	NP_001357065.1	Q8WYB5-1
	KAT6B	NM_001370137.1		c.5213C>T	p.Thr1738Ile	missense	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.5213C>T	p.Thr1738Ile	missense	Exon 18 of 18	ENSP00000287239.4	Q8WYB5-1
	KAT6B	ENST00000372711.2	TSL:1	c.4664C>T	p.Thr1555Ile	missense	Exon 18 of 18	ENSP00000361796.1	Q8WYB5-2
	KAT6B	ENST00000648725.1		c.5213C>T	p.Thr1738Ile	missense	Exon 18 of 18	ENSP00000497841.1	Q8WYB5-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461876 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	Clubfoot;C0010417:Cryptorchidism;C0020534:Hypertelorism;C0424503:Abnormal facial shape;C0426886:Tapered finger;C1854114:Short nose;C3714756:Intellectual disability;C4021771:Short distal phalanx of toe;C5702564:Neuropathic spinal arthropathy (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	18
DANN	Benign	0.93
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.080
FATHMM_MKL	Benign	0.72	D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.61
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.28
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.058	T
Polyphen		0.18	B
Vest4		0.23
MutPred		0.11		Loss of glycosylation at T1738 (P = 0.0753)
MVP		0.23
MPC		0.23
ClinPred		0.62	D
GERP RS		2.2
Varity_R		0.19
gMVP		0.38
Mutation Taster		=2/98	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: rs1554846212; hg19: chr10-76789795;