X-44873579-ACCGCCGCCGCTG-A

Variant names:

• chrX-44873579-ACCGCCGCCGCTG-A
• rs749062014
• NM_001291415.2:c.40_51delGCCGCCGCCGCT

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP3 BP6_Moderate BS2

The NM_001291415.2(KDM6A):​c.40_51delGCCGCCGCCGCT​(p.Ala14_Ala17del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.0000418 in 1,197,289 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000028 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000043 (0 hom. 13 hem.)
• Consequence: KDM6A NM_001291415.2 conservative_inframe_deletion
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.43
• Publications: 0 publications found

Genes affected

KDM6A (HGNC:12637): (lysine demethylase 6A) This gene is located on the X chromosome and is the corresponding locus to a Y-linked gene which encodes a tetratricopeptide repeat (TPR) protein. The encoded protein of this gene contains a JmjC-domain and catalyzes the demethylation of tri/dimethylated histone H3. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Apr 2014]

KDM6A Gene-Disease associations (from GenCC):

• Kabuki syndrome 2

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• Kabuki syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001291415.2
• BP6: Variant X-44873579-ACCGCCGCCGCTG-A is Benign according to our data. Variant chrX-44873579-ACCGCCGCCGCTG-A is described in ClinVar as Benign. ClinVar VariationId is 1601404.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 47 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291415.2. 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
	KDM6A	NM_001291415.2	MANE Select	c.40_51delGCCGCCGCCGCT	p.Ala14_Ala17del	conservative_inframe_deletion	Exon 1 of 30	NP_001278344.1	A0A087X0R0
	KDM6A	NM_001419809.1		c.40_51delGCCGCCGCCGCT	p.Ala14_Ala17del	conservative_inframe_deletion	Exon 1 of 31	NP_001406738.1
	KDM6A	NM_001419810.1		c.40_51delGCCGCCGCCGCT	p.Ala14_Ala17del	conservative_inframe_deletion	Exon 1 of 30	NP_001406739.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM6A	ENST00000611820.5	TSL:1 MANE Select	c.40_51delGCCGCCGCCGCT	p.Ala14_Ala17del	conservative_inframe_deletion	Exon 1 of 30	ENSP00000483595.2	A0A087X0R0
	KDM6A	ENST00000382899.9	TSL:1	c.40_51delGCCGCCGCCGCT	p.Ala14_Ala17del	conservative_inframe_deletion	Exon 1 of 29	ENSP00000372355.6	F8W8R6
	KDM6A	ENST00000377967.9	TSL:1	c.40_51delGCCGCCGCCGCT	p.Ala14_Ala17del	conservative_inframe_deletion	Exon 1 of 29	ENSP00000367203.4	O15550

Frequencies

GnomAD3 genomes AF: 0.0000280 AC: 3 AN: 107179 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000345

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000388

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000437 AC: 7 AN: 160255 AF XY: 0.0000900

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000382

Gnomad ASJ exome AF: 0.000143

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000583

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000431 AC: 47 AN: 1090060 Hom.: 0 AF XY: 0.0000363 AC XY: 13 AN XY: 358010

African (AFR) AF: 0.0000380 AC: 1 AN: 26284

American (AMR) AF: 0.0000291 AC: 1 AN: 34405

Ashkenazi Jewish (ASJ) AF: 0.0000520 AC: 1 AN: 19244

East Asian (EAS) AF: 0.00 AC: 0 AN: 29816

South Asian (SAS) AF: 0.0000561 AC: 3 AN: 53437

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38468

Middle Eastern (MID) AF: 0.000257 AC: 1 AN: 3891

European-Non Finnish (NFE) AF: 0.0000441 AC: 37 AN: 838872

Other (OTH) AF: 0.0000657 AC: 3 AN: 45643

GnomAD4 genome AF: 0.0000280 AC: 3 AN: 107229 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 31259

African (AFR) AF: 0.0000344 AC: 1 AN: 29053

American (AMR) AF: 0.00 AC: 0 AN: 10261

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2587

East Asian (EAS) AF: 0.00 AC: 0 AN: 3339

South Asian (SAS) AF: 0.00 AC: 0 AN: 2528

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 194

European-Non Finnish (NFE) AF: 0.0000388 AC: 2 AN: 51543

Other (OTH) AF: 0.00 AC: 0 AN: 1467

Alfa AF: 0.0000868 Hom.: 3

Bravo AF: 0.0000604

Asia WGS AF: 0.00120 AC: 3 AN: 2519

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Kabuki syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.4
Mutation Taster		=185/15	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs749062014; hg19: chrX-44732825; COSMIC: COSV65038041;