rs587778421

Variant names:

• chrX-45053895-A-G
• rs587778421
• NM_001291415.2:c.815A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4 BS2

The NM_001291415.2(KDM6A):​c.815A>G​(p.Tyr272Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000459 in 1,090,047 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 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. Y272H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000046 (0 hom. 1 hem.)
• Consequence: KDM6A NM_001291415.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:1
• Conservation: PhyloP100: 5.56
• Publications: 2 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34401387).
• BS2: High AC in GnomAdExome4 at 5 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.815A>G	p.Tyr272Cys	missense	Exon 10 of 30	NP_001278344.1
	KDM6A	NM_001419809.1		c.815A>G	p.Tyr272Cys	missense	Exon 10 of 31	NP_001406738.1
	KDM6A	NM_001419810.1		c.815A>G	p.Tyr272Cys	missense	Exon 10 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.815A>G	p.Tyr272Cys	missense	Exon 10 of 30	ENSP00000483595.2
	KDM6A	ENST00000382899.9	TSL:1	c.815A>G	p.Tyr272Cys	missense	Exon 10 of 29	ENSP00000372355.6
	KDM6A	ENST00000377967.9	TSL:1	c.815A>G	p.Tyr272Cys	missense	Exon 10 of 29	ENSP00000367203.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000459 AC: 5 AN: 1090047 Hom.: 0 Cov.: 27 AF XY: 0.00000281 AC XY: 1 AN XY: 355923

African (AFR) AF: 0.00 AC: 0 AN: 26252

American (AMR) AF: 0.00 AC: 0 AN: 35197

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19327

East Asian (EAS) AF: 0.00 AC: 0 AN: 30126

South Asian (SAS) AF: 0.00 AC: 0 AN: 53943

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40523

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4117

European-Non Finnish (NFE) AF: 0.00000599 AC: 5 AN: 834728

Other (OTH) AF: 0.00 AC: 0 AN: 45834

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Kabuki syndrome 2 (1)
-	1	-	not provided (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.099	T
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.14	N
PhyloP100		5.6
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.1	D
REVEL	Benign	0.13
Sift	Benign	0.36	T
Sift4G	Benign	0.35	T
Polyphen		0.0020	B
Vest4		0.44
MutPred		0.40		Gain of catalytic residue at L273 (P = 0.011)
MVP		0.29
MPC		0.97
ClinPred		0.85	D
GERP RS		5.4
Varity_R		0.65
gMVP		0.54
Mutation Taster		=90/10	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: rs587778421; hg19: chrX-44913140;