NM_001291415.2:c.3267G>C

Variant names:

• chrX-45079318-G-C
• rs20539
• NM_001291415.2:c.3267G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001291415.2(KDM6A):​c.3267G>C​(p.Gln1089His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q1089Q) has been classified as Benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: KDM6A NM_001291415.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.88
• Publications: 26 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDM6A	NM_001291415.2	c.3267G>C	p.Gln1089His	missense_variant	Exon 21 of 30	ENST00000611820.5	NP_001278344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KDM6A	ENST00000611820.5	c.3267G>C	p.Gln1089His	missense_variant	Exon 21 of 30	1	NM_001291415.2	ENSP00000483595.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	.;T;.;T;D
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.53	D;D;D;D;D
MetaSVM	Benign	-0.39	T
MutationAssessor	Pathogenic	3.2	.;.;.;.;M
PhyloP100		1.9
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-4.0	.;.;.;.;D
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	.;.;.;.;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		1.0	.;.;.;.;D
Vest4		0.58
MVP		0.82
MPC		1.5
ClinPred		1.0	D
GERP RS		0.23
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.65
Mutation Taster		=63/37	polymorphism

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: rs20539; hg19: chrX-44938563;