rs786205676

Variant names:

• chrX-45070166-CACAA-C
• rs786205676
• NM_001291415.2:c.2671_2674delAACA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001291415.2(KDM6A):​c.2671_2674delAACA​(p.Asn891ValfsTer27) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: KDM6A NM_001291415.2 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.88
• Publications: 1 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 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-45070166-CACAA-C is Pathogenic according to our data. Variant chrX-45070166-CACAA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 190247.Status of the report is criteria_provided_single_submitter, 1 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.2671_2674delAACA	p.Asn891ValfsTer27	frameshift	Exon 18 of 30	NP_001278344.1	A0A087X0R0
	KDM6A	NM_001419809.1		c.2671_2674delAACA	p.Asn891ValfsTer27	frameshift	Exon 18 of 31	NP_001406738.1
	KDM6A	NM_001419810.1		c.2569_2572delAACA	p.Asn857ValfsTer27	frameshift	Exon 17 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.2671_2674delAACA	p.Asn891ValfsTer27	frameshift	Exon 18 of 30	ENSP00000483595.2	A0A087X0R0
	KDM6A	ENST00000382899.9	TSL:1	c.2536_2539delAACA	p.Asn846ValfsTer27	frameshift	Exon 17 of 29	ENSP00000372355.6	F8W8R6
	KDM6A	ENST00000377967.9	TSL:1	c.2515_2518delAACA	p.Asn839ValfsTer27	frameshift	Exon 17 of 29	ENSP00000367203.4	O15550

Frequencies

GnomAD3 genomes Cov.: 22

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.9
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs786205676;

hg19: chrX-44929411;

COSMIC: COSV65039572;