rs548231613

Variant names:

• chr8-41933168-CTGCGGCTGCTGT-C
• rs548231613
• NM_006766.5:c.5040_5051delACAGCAGCCGCA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM4 BP6_Very_Strong BS2

The NM_006766.5(KAT6A):​c.5040_5051delACAGCAGCCGCA​(p.Gln1681_Gln1684del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00129 in 1,597,142 control chromosomes in the GnomAD database, including 5 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00094 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0013 (5 hom.)
• Consequence: KAT6A NM_006766.5 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.99
• Publications: 1 publications found

Genes affected

KAT6A (HGNC:13013): (lysine acetyltransferase 6A) This gene encodes a member of the MOZ, YBFR2, SAS2, TIP60 family of histone acetyltransferases. The protein is composed of a nuclear localization domain, a double C2H2 zinc finger domain that binds to acetylated histone tails, a histone acetyl-transferase domain, a glutamate/aspartate-rich region, and a serine- and methionine-rich transactivation domain. It is part of a complex that acetylates lysine-9 residues in histone 3, and in addition, it acts as a co-activator for several transcription factors. Allelic variants of this gene are associated with an autosomal dominant form of cognitive disability. Chromosomal translocations of this gene are associated with acute myeloid leukemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2017]

KAT6A Gene-Disease associations (from GenCC):

• autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Illumina, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_006766.5.
• BP6: Variant 8-41933168-CTGCGGCTGCTGT-C is Benign according to our data. Variant chr8-41933168-CTGCGGCTGCTGT-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 589281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 143 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006766.5. 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
	KAT6A	NM_006766.5	MANE Select	c.5040_5051delACAGCAGCCGCA	p.Gln1681_Gln1684del	disruptive_inframe_deletion	Exon 17 of 17	NP_006757.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KAT6A	ENST00000265713.8	TSL:1 MANE Select	c.5040_5051delACAGCAGCCGCA	p.Gln1681_Gln1684del	disruptive_inframe_deletion	Exon 17 of 17	ENSP00000265713.2
	KAT6A	ENST00000406337.6	TSL:5	c.5046_5057delACAGCAGCCGCA	p.Gln1683_Gln1686del	disruptive_inframe_deletion	Exon 18 of 18	ENSP00000385888.2
	KAT6A	ENST00000396930.4	TSL:5	c.5040_5051delACAGCAGCCGCA	p.Gln1681_Gln1684del	disruptive_inframe_deletion	Exon 18 of 18	ENSP00000380136.3

Frequencies

GnomAD3 genomes AF: 0.000942 AC: 143 AN: 151738 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000969

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00177

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000884 AC: 196 AN: 221694 AF XY: 0.000801

Gnomad AFR exome AF: 0.0000728

Gnomad AMR exome AF: 0.000931

Gnomad ASJ exome AF: 0.000212

Gnomad EAS exome AF: 0.000709

Gnomad FIN exome AF: 0.000300

Gnomad NFE exome AF: 0.00138

Gnomad OTH exome AF: 0.00162

GnomAD4 exome AF: 0.00133 AC: 1918 AN: 1445286 Hom.: 5 AF XY: 0.00128 AC XY: 917 AN XY: 717976

African (AFR) AF: 0.000210 AC: 7 AN: 33296

American (AMR) AF: 0.000991 AC: 43 AN: 43390

Ashkenazi Jewish (ASJ) AF: 0.000271 AC: 7 AN: 25842

East Asian (EAS) AF: 0.000254 AC: 10 AN: 39388

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 85018

European-Finnish (FIN) AF: 0.000375 AC: 18 AN: 47970

Middle Eastern (MID) AF: 0.000227 AC: 1 AN: 4414

European-Non Finnish (NFE) AF: 0.00159 AC: 1754 AN: 1106148

Other (OTH) AF: 0.00129 AC: 77 AN: 59820

GnomAD4 genome AF: 0.000942 AC: 143 AN: 151856 Hom.: 0 Cov.: 31 AF XY: 0.00104 AC XY: 77 AN XY: 74220

African (AFR) AF: 0.0000967 AC: 4 AN: 41382

American (AMR) AF: 0.00105 AC: 16 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.000388 AC: 2 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00177 AC: 120 AN: 67898

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.00111 Hom.: 0

Bravo AF: 0.000941

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.0
Mutation Taster		=197/3	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs548231613; hg19: chr8-41790686;