X-44873571-C-G

Variant names:

• chrX-44873571-C-G
• rs770931883
• NM_001291415.2:c.20C>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_001291415.2(KDM6A):​c.20C>G​(p.Ser7Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000366 in 1,093,220 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000037 (0 hom. 2 hem.)
• Consequence: KDM6A NM_001291415.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.76
• 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: 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 -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827
• BS2: High Hemizygotes in GnomAdExome4 at 2 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.20C>G	p.Ser7Trp	missense	Exon 1 of 30	NP_001278344.1	A0A087X0R0
	KDM6A	NM_001419809.1		c.20C>G	p.Ser7Trp	missense	Exon 1 of 31	NP_001406738.1
	KDM6A	NM_001419810.1		c.20C>G	p.Ser7Trp	missense	Exon 1 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.20C>G	p.Ser7Trp	missense	Exon 1 of 30	ENSP00000483595.2	A0A087X0R0
	KDM6A	ENST00000382899.9	TSL:1	c.20C>G	p.Ser7Trp	missense	Exon 1 of 29	ENSP00000372355.6	F8W8R6
	KDM6A	ENST00000377967.9	TSL:1	c.20C>G	p.Ser7Trp	missense	Exon 1 of 29	ENSP00000367203.4	O15550

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00 AC: 0 AN: 166150 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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000366 AC: 4 AN: 1093220 Hom.: 0 Cov.: 32 AF XY: 0.00000555 AC XY: 2 AN XY: 360264

African (AFR) AF: 0.00 AC: 0 AN: 26343

American (AMR) AF: 0.00 AC: 0 AN: 34872

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19302

East Asian (EAS) AF: 0.00 AC: 0 AN: 30043

South Asian (SAS) AF: 0.00 AC: 0 AN: 53723

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38782

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4007

European-Non Finnish (NFE) AF: 0.00000476 AC: 4 AN: 840369

Other (OTH) AF: 0.00 AC: 0 AN: 45779

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000170 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		3.8
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.67
MutPred		0.44		Loss of glycosylation at S7 (P = 0.0168)
MVP		0.95
MPC		2.2
ClinPred		0.95	D
GERP RS		4.4
PromoterAI		-0.0084	Neutral
Varity_R		0.87
gMVP		0.90
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: rs770931883; hg19: chrX-44732817; COSMIC: COSV100937998;