X-45051714-A-T

Variant names:

• chrX-45051714-A-T
• rs587778423
• NM_001291415.2:c.660A>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_001291415.2(KDM6A):​c.660A>T​(p.Lys220Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000113 in 1,146,599 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. K220K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000012 (0 hom. 4 hem.)
• Consequence: KDM6A NM_001291415.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4 O:1
• Conservation: PhyloP100: 4.28
• 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• Kabuki syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0000116 (12/1034570) while in subpopulation AFR AF = 0.000318 (8/25187). AF 95% confidence interval is 0.000158. There are 0 homozygotes in GnomAdExome4. There are 4 alleles in the male GnomAdExome4 subpopulation. Median coverage is 21. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 12 XL,AD gene.

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.660A>T	p.Lys220Asn	missense	Exon 9 of 30	NP_001278344.1	A0A087X0R0
	KDM6A	NM_001419809.1		c.660A>T	p.Lys220Asn	missense	Exon 9 of 31	NP_001406738.1
	KDM6A	NM_001419810.1		c.660A>T	p.Lys220Asn	missense	Exon 9 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.660A>T	p.Lys220Asn	missense	Exon 9 of 30	ENSP00000483595.2	A0A087X0R0
	KDM6A	ENST00000382899.9	TSL:1	c.660A>T	p.Lys220Asn	missense	Exon 9 of 29	ENSP00000372355.6	F8W8R6
	KDM6A	ENST00000377967.9	TSL:1	c.660A>T	p.Lys220Asn	missense	Exon 9 of 29	ENSP00000367203.4	O15550

Frequencies

GnomAD3 genomes AF: 0.00000893 AC: 1 AN: 112029 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD2 exomes AF: 0.00000581 AC: 1 AN: 172124 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000386

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 12 AN: 1034570 Hom.: 0 Cov.: 21 AF XY: 0.0000125 AC XY: 4 AN XY: 318728

African (AFR) AF: 0.000318 AC: 8 AN: 25187

American (AMR) AF: 0.0000291 AC: 1 AN: 34310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18757

East Asian (EAS) AF: 0.00 AC: 0 AN: 29861

South Asian (SAS) AF: 0.00 AC: 0 AN: 51405

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40347

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3089

European-Non Finnish (NFE) AF: 0.00000127 AC: 1 AN: 787653

Other (OTH) AF: 0.0000455 AC: 2 AN: 43961

GnomAD4 genome AF: 0.00000893 AC: 1 AN: 112029 Hom.: 0 Cov.: 23 AF XY: 0.0000293 AC XY: 1 AN XY: 34183

African (AFR) AF: 0.0000325 AC: 1 AN: 30805

American (AMR) AF: 0.00 AC: 0 AN: 10574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2658

East Asian (EAS) AF: 0.00 AC: 0 AN: 3576

South Asian (SAS) AF: 0.00 AC: 0 AN: 2709

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6044

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53233

Other (OTH) AF: 0.00 AC: 0 AN: 1505

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Kabuki syndrome 2 (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	Kabuki syndrome 1 (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.050	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.3
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Benign	0.14
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.046	D
Polyphen		0.22	B
Vest4		0.54
MutPred		0.43		Loss of ubiquitination at K220 (P = 0.0155)
MVP		0.52
MPC		1.9
ClinPred		0.92	D
GERP RS		3.1
Varity_R		0.84
gMVP		0.49
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs587778423; hg19: chrX-44910959;