X-45063737-C-T

Variant names:

• chrX-45063737-C-T
• rs112725812
• NM_001291415.2:c.1999C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001291415.2(KDM6A):​c.1999C>T​(p.Leu667Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000183 in 1,093,362 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L667V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: KDM6A NM_001291415.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.09
• Publications: 14 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• Kabuki syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14933178).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291415.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM6A	NM_001291415.2	MANE Select	c.1999C>T	p.Leu667Phe	missense	Exon 17 of 30	NP_001278344.1	A0A087X0R0
	KDM6A	NM_001419809.1		c.1999C>T	p.Leu667Phe	missense	Exon 17 of 31	NP_001406738.1
	KDM6A	NM_001419810.1		c.1897C>T	p.Leu633Phe	missense	Exon 16 of 30	NP_001406739.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM6A	ENST00000611820.5	TSL:1 MANE Select	c.1999C>T	p.Leu667Phe	missense	Exon 17 of 30	ENSP00000483595.2	A0A087X0R0
	KDM6A	ENST00000382899.9	TSL:1	c.1864C>T	p.Leu622Phe	missense	Exon 16 of 29	ENSP00000372355.6	F8W8R6
	KDM6A	ENST00000377967.9	TSL:1	c.1843C>T	p.Leu615Phe	missense	Exon 16 of 29	ENSP00000367203.4	O15550

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.00000580 AC: 1 AN: 172315 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000132

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1093362 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 359120

African (AFR) AF: 0.00 AC: 0 AN: 26319

American (AMR) AF: 0.00 AC: 0 AN: 34774

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19324

East Asian (EAS) AF: 0.00 AC: 0 AN: 30080

South Asian (SAS) AF: 0.00 AC: 0 AN: 53396

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40227

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4133

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 839172

Other (OTH) AF: 0.0000218 AC: 1 AN: 45937

GnomAD4 genome Cov.: 22

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Kabuki syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.0066	T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.46	N
PhyloP100		4.1
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.087
Sift	Benign	0.058	T
Sift4G	Benign	0.69	T
Polyphen		0.0	B
Vest4		0.36
MVP		0.33
MPC		0.12
ClinPred		0.17	T
GERP RS		5.3
Varity_R		0.11
gMVP		0.38
Mutation Taster		=88/12	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: rs112725812; hg19: chrX-44922982;