chrX-45037659-A-T

Variant names:

• chrX-45037659-A-T
• rs200602649
• NM_001291415.2:c.624A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001291415.2(KDM6A):​c.624A>T​(p.Gln208His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q208Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: KDM6A NM_001291415.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.172
• Publications: 0 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4070761).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDM6A	NM_001291415.2	c.624A>T	p.Gln208His	missense_variant	Exon 8 of 30	ENST00000611820.5	NP_001278344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KDM6A	ENST00000611820.5	c.624A>T	p.Gln208His	missense_variant	Exon 8 of 30	1	NM_001291415.2	ENSP00000483595.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	3.2
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	.;T;.;T;D;.
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.41	T;T;T;T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.2	.;.;.;.;M;.
PhyloP100		0.17
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.4	.;.;.;.;D;.
REVEL	Benign	0.22
Sift	Benign	0.041	.;.;.;.;D;.
Sift4G	Uncertain	0.011	D;D;D;D;D;D
Polyphen		0.42	.;.;.;.;B;.
Vest4		0.59
MutPred		0.52		.;.;.;.;Loss of stability (P = 0.2317);Loss of stability (P = 0.2317);
MVP		0.43
MPC		0.81
ClinPred		0.98	D
GERP RS		-0.58
Varity_R		0.67
gMVP		0.44
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs200602649; hg19: chrX-44896904;