rs1556328781

Variant names:

• chrX-45069754-C-CCTCT
• rs1556328781
• NM_001291415.2:c.2257_2260dupTCTC

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.2257_2260dupTCTC​(p.His754LeufsTer29) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. 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:1
• Conservation: PhyloP100: 1.71
• 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: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• 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-45069754-C-CCTCT is Pathogenic according to our data. Variant chrX-45069754-C-CCTCT is described in ClinVar as Pathogenic. ClinVar VariationId is 471947.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM6A	NM_001291415.2	MANE Select	c.2257_2260dupTCTC	p.His754LeufsTer29	frameshift	Exon 18 of 30	NP_001278344.1
	KDM6A	NM_001419809.1		c.2257_2260dupTCTC	p.His754LeufsTer29	frameshift	Exon 18 of 31	NP_001406738.1
	KDM6A	NM_001419810.1		c.2155_2158dupTCTC	p.His720LeufsTer29	frameshift	Exon 17 of 30	NP_001406739.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM6A	ENST00000611820.5	TSL:1 MANE Select	c.2257_2260dupTCTC	p.His754LeufsTer29	frameshift	Exon 18 of 30	ENSP00000483595.2
	KDM6A	ENST00000382899.9	TSL:1	c.2122_2125dupTCTC	p.His709LeufsTer29	frameshift	Exon 17 of 29	ENSP00000372355.6
	KDM6A	ENST00000377967.9	TSL:1	c.2101_2104dupTCTC	p.His702LeufsTer29	frameshift	Exon 17 of 29	ENSP00000367203.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Kabuki syndrome 2 Pathogenic:1

Apr 01, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, loss-of-function variants in KDM6A are known to be pathogenic (PMID: 23076834). This sequence change inserts 4 nucleotides in exon 17 of the KDM6A mRNA (c.2101_2104dupTCTC), causing a frameshift at codon 702. This creates a premature translational stop signal (p.His702Leufs*29) and is expected to result in an absent or disrupted protein product.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1556328781; hg19: chrX-44928999;