10-74842858-A-G

Variant names:

• chr10-74842858-A-G
• NM_012330.4:c.1A>G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Supporting PM2 PP5_Moderate

The NM_012330.4(KAT6B):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KAT6B NM_012330.4 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.95

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 Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 285 codons. Genomic position: 74970026. Lost 0.137 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-74842858-A-G is Pathogenic according to our data. Variant chr10-74842858-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1708059.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KAT6B	NM_012330.4	c.1A>G	p.Met1?	start_lost	Exon 3 of 18	ENST00000287239.10	NP_036462.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KAT6B	ENST00000287239.10	c.1A>G	p.Met1?	start_lost	Exon 3 of 18	1	NM_012330.4	ENSP00000287239.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Blepharophimosis - intellectual disability syndrome, SBBYS type Pathogenic:1

Jul 12, 2022

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Uncertain	0.55	.;D;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.39	D
PROVEAN	Uncertain	-3.4	.;.;.;.;.;D;.;.;.;.;.;.;.;.;D;.;D;D;.;.;.;.;.;.;D;.;.
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	.;.;.;.;.;D;.;.;.;.;.;.;.;.;D;.;D;D;.;.;.;.;.;.;D;.;.
Sift4G	Pathogenic	0.0	.;.;.;.;.;D;.;.;.;.;.;.;.;.;D;.;D;D;.;.;.;.;.;.;D;.;.
Polyphen		0.97, 0.98	.;D;.;D;D;D;.;.;.;.;.;.;D;.;D;.;D;D;.;.;.;.;.;.;D;.;.
Vest4		0.81, 0.80, 0.81, 0.86, 0.87
MutPred		0.91		Gain of sheet (P = 0.0073);Gain of sheet (P = 0.0073);Gain of sheet (P = 0.0073);Gain of sheet (P = 0.0073);Gain of sheet (P = 0.0073);Gain of sheet (P = 0.0073);Gain of sheet (P = 0.0073);Gain of sheet (P = 0.0073);Gain of sheet (P = 0.0073);Gain of sheet (P = 0.0073);Gain of sheet (P = 0.0073);Gain of sheet (P = 0.0073);Gain of sheet (P = 0.0073);Gain of sheet (P = 0.0073);Gain of sheet (P = 0.0073);Gain of sheet (P = 0.0073);Gain of sheet (P = 0.0073);Gain of sheet (P = 0.0073);Gain of sheet (P = 0.0073);Gain of sheet (P = 0.0073);Gain of sheet (P = 0.0073);Gain of sheet (P = 0.0073);Gain of sheet (P = 0.0073);Gain of sheet (P = 0.0073);Gain of sheet (P = 0.0073);Gain of sheet (P = 0.0073);Gain of sheet (P = 0.0073);
MVP		0.95
ClinPred		0.99	D
GERP RS		6.2
Varity_R		0.82
gMVP		0.62

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-76602616;