X-45070166-CACAA-C

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: 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-45070166-CACAA-C is Pathogenic according to our data. Variant chrX-45070166-CACAA-C is described in ClinVar as [Pathogenic]. Clinvar id is 190247.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDM6A	NM_001291415.2	c.2671_2674delAACA	p.Asn891ValfsTer27	frameshift_variant	Exon 18 of 30	ENST00000611820.5	NP_001278344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KDM6A	ENST00000611820.5	c.2671_2674delAACA	p.Asn891ValfsTer27	frameshift_variant	Exon 18 of 30	1	NM_001291415.2	ENSP00000483595.2

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

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Dec 31, 2018

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the KDM6A gene demonstrated a four base pair deletion in exon 17, c.2515_2518del. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 26 amino acids downstream of the mutation, p.Asn839Valfs*27. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated KDM6A protein with potentially abnormal function. This pathogenic sequence change has previously been described in a family with KDM6A-related Kabuki syndrome (PMID: 24664873). In this family, two brothers with Kabuki syndrome were found to be hemizygous for the c.2515_2518del sequence change; their mother and maternal grandmother were heterozygous for the c.2515_2518del pathogenic sequence change and exhibited mild features of Kabuki syndrome." DNA sequence analysis of the KDM6A gene demonstrated a four base pair deletion in exon 17, c.2515_2518del. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 26 amino acids downstream of the mutation, p.Asn839Valfs*27. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated KDM6A protein with potentially abnormal function. This pathogenic sequence change has previously been described in a family with KDM6A-related Kabuki syndrome (PMID: 24664873). In this family, two brothers with Kabuki syndrome were found to be hemizygous for the c.2515_2518del sequence change; their mother and maternal grandmother were heterozygous for the c.2515_2518del pathogenic sequence change and exhibited mild features of Kabuki syndrome. -

Kabuki syndrome 2 Pathogenic:1

May 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs786205676; hg19: chrX-44929411; COSMIC: COSV65039572;