rs786205676
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001291415.2(KDM6A):c.2671_2674del(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
NM_001291415.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.88
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 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. Variant chrX-45070166-CACAA-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KDM6A | NM_001291415.2 | c.2671_2674del | p.Asn891ValfsTer27 | frameshift_variant | 18/30 | ENST00000611820.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KDM6A | ENST00000611820.5 | c.2671_2674del | p.Asn891ValfsTer27 | frameshift_variant | 18/30 | 1 | NM_001291415.2 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD3 genomes
?
Cov.:
22
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 22
GnomAD4 genome
?
Cov.:
22
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 31, 2018 | 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
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2014 | - - |
Computational scores
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at