X-44873574-TCGCTACCGCCGC-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP3

The NM_001291415.2(KDM6A):c.28_39del(p.Thr10_Ala13del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00000458 in 1,092,546 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L8L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000046 (0 hom. 2 hem.)
• Consequence: KDM6A NM_001291415.2 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.92

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001291415.2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KDM6A	NM_001291415.2	c.28_39del	p.Thr10_Ala13del	inframe_deletion	1/30	ENST00000611820.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KDM6A	ENST00000611820.5	c.28_39del	p.Thr10_Ala13del	inframe_deletion	1/30	1	NM_001291415.2	P4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000181 AC: 3 AN: 166020 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 59016

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000141

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000547

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000140

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000458 AC: 5 AN: 1092546 Hom.: 0 AF XY: 0.00000556 AC XY: 2 AN XY: 359818

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000518

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000372

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Kabuki syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 22, 2022

This variant has not been reported in the literature in individuals affected with KDM6A-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant is present in population databases (rs769370817, gnomAD 0.01%). This variant, c.28_39del, results in the deletion of 4 amino acid(s) of the KDM6A protein (p.Thr10_Ala13del), but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs769370817; hg19: chrX-44732820;