rs587778422

Variant names:

• chrX-45107480-A-T
• rs587778422
• NM_001291415.2:c.4105A>T

Variant summary

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

The NM_001291415.2(KDM6A):​c.4105A>T​(p.Ile1369Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: KDM6A NM_001291415.2 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 2.39
• Publications: 1 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

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.4105A>T	p.Ile1369Phe	missense	Exon 28 of 30	NP_001278344.1
	KDM6A	NM_001419809.1		c.4213A>T	p.Ile1405Phe	missense	Exon 29 of 31	NP_001406738.1
	KDM6A	NM_001419810.1		c.4111A>T	p.Ile1371Phe	missense	Exon 28 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.4105A>T	p.Ile1369Phe	missense	Exon 28 of 30	ENSP00000483595.2
	KDM6A	ENST00000382899.9	TSL:1	c.3970A>T	p.Ile1324Phe	missense	Exon 27 of 29	ENSP00000372355.6
	KDM6A	ENST00000377967.9	TSL:1	c.3949A>T	p.Ile1317Phe	missense	Exon 27 of 29	ENSP00000367203.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions as Germline

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Benign	-0.46
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.13	T
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.31	T
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-1.1	T
PhyloP100		2.4
Sift4G	Uncertain	0.0030	D
Vest4		0.68
MVP		0.92
ClinPred		0.77	D
GERP RS		5.5
Varity_R		0.67
Mutation Taster		=53/47	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: rs587778422; hg19: chrX-44966725;