rs1135401809

Variant names:

• chrX-45076827-G-A
• rs1135401809
• NM_001291415.2:c.2988+1G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-45076827-G-A
• chrX-45076827-G-C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001291415.2(KDM6A):​c.2988+1G>A variant causes a splice donor, intron 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: KDM6A NM_001291415.2 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 9.60
• Publications: 2 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-45076827-G-A is Pathogenic according to our data. Variant chrX-45076827-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 545065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2988+1G>A		splice_donor intron	N/A	NP_001278344.1	A0A087X0R0
	KDM6A	NM_001419809.1		c.2988+1G>A		splice_donor intron	N/A	NP_001406738.1
	KDM6A	NM_001419810.1		c.2886+1G>A		splice_donor intron	N/A	NP_001406739.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM6A	ENST00000611820.5	TSL:1 MANE Select	c.2988+1G>A		splice_donor intron	N/A	ENSP00000483595.2	A0A087X0R0
	KDM6A	ENST00000382899.9	TSL:1	c.2853+1G>A		splice_donor intron	N/A	ENSP00000372355.6	F8W8R6
	KDM6A	ENST00000377967.9	TSL:1	c.2832+1G>A		splice_donor intron	N/A	ENSP00000367203.4	O15550

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1087077 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 354033

African (AFR) AF: 0.00 AC: 0 AN: 26163

American (AMR) AF: 0.00 AC: 0 AN: 35158

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19273

East Asian (EAS) AF: 0.00 AC: 0 AN: 30098

South Asian (SAS) AF: 0.00 AC: 0 AN: 53787

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40461

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3441

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 833041

Other (OTH) AF: 0.00 AC: 0 AN: 45655

GnomAD4 genome Cov.: 21

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Kabuki syndrome 2 (1)
-	-	-	Neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	30
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		9.6
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
Splicevardb		3.0
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: -1

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

Other links and lift over

dbSNP: rs1135401809; hg19: chrX-44936072; COSMIC: COSV65037460;