rs763587293

Variant names:

• chrX-45062742-A-C
• rs763587293
• NM_001291415.2:c.1677A>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001291415.2(KDM6A):​c.1677A>C​(p.Gln559His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 112,478 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000029 (0 hom. 2 hem.)
  • Failed GnomAD Quality Control
• Consequence: KDM6A NM_001291415.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 2.18

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19937742).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDM6A	NM_001291415.2	c.1677A>C	p.Gln559His	missense_variant	Exon 16 of 30	ENST00000611820.5	NP_001278344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KDM6A	ENST00000611820.5	c.1677A>C	p.Gln559His	missense_variant	Exon 16 of 30	1	NM_001291415.2	ENSP00000483595.2

Frequencies

GnomAD3 genomes AF: 0.0000267 AC: 3 AN: 112478 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34616

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000188

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000657

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000289 AC: 3 AN: 1039225 Hom.: 0 Cov.: 23 AF XY: 0.00000639 AC XY: 2 AN XY: 312901

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000254

Gnomad4 OTH exome AF: 0.0000226

GnomAD4 genome AF: 0.0000267 AC: 3 AN: 112478 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34616

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000188

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000657

Bravo AF: 0.000162

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Kabuki syndrome 2 Uncertain:2

Oct 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 507 of the KDM6A protein (p.Gln507His). This variant is present in population databases (rs763587293, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with KDM6A-related conditions. ClinVar contains an entry for this variant (Variation ID: 520720). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KDM6A protein function. 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. -

Oct 25, 2018

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2. This variant was detected in hemizygous state. -

Inborn genetic diseases Uncertain:1

Aug 06, 2015

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Apr 09, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.031	.;.;T;T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T;T;T;T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.20	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.2	.;.;.;M
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.4	.;.;.;N
REVEL	Benign	0.074
Sift	Uncertain	0.0010	.;.;.;D
Sift4G	Benign	0.099	T;T;D;T
Polyphen		0.0010	.;.;.;B
Vest4		0.26
MVP		0.48
MPC		0.11
ClinPred		0.87	D
GERP RS		3.2
Varity_R		0.40
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs763587293; hg19: chrX-44921987; COSMIC: COSV104687003;