X-45079318-G-A

Variant names:

• chrX-45079318-G-A
• rs20539
• NM_001291415.2:c.3267G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The ENST00000611820.5(KDM6A):​c.3267G>A​(p.Gln1089Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.198 in 1,189,505 control chromosomes in the GnomAD database, including 18,401 homozygotes. There are 76,408 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (1620 hom., 5527 hem., cov: 22)
  • Exomes 𝑓: 0.20 (16781 hom. 70881 hem.)
• Consequence: KDM6A ENST00000611820.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.88
• Publications: 26 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.156).
• BP6: Variant X-45079318-G-A is Benign according to our data. Variant chrX-45079318-G-A is described in ClinVar as Benign. ClinVar VariationId is 158689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.88 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.356 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000611820.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM6A	NM_001291415.2	MANE Select	c.3267G>A	p.Gln1089Gln	synonymous	Exon 21 of 30	NP_001278344.1
	KDM6A	NM_001419809.1		c.3267G>A	p.Gln1089Gln	synonymous	Exon 21 of 31	NP_001406738.1
	KDM6A	NM_001419810.1		c.3165G>A	p.Gln1055Gln	synonymous	Exon 20 of 30	NP_001406739.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM6A	ENST00000611820.5	TSL:1 MANE Select	c.3267G>A	p.Gln1089Gln	synonymous	Exon 21 of 30	ENSP00000483595.2
	KDM6A	ENST00000382899.9	TSL:1	c.3132G>A	p.Gln1044Gln	synonymous	Exon 20 of 29	ENSP00000372355.6
	KDM6A	ENST00000377967.9	TSL:1	c.3111G>A	p.Gln1037Gln	synonymous	Exon 20 of 29	ENSP00000367203.4

Frequencies

GnomAD3 genomes AF: 0.169 AC: 18636 AN: 110287 Hom.: 1626 Cov.: 22

Gnomad AFR AF: 0.0313

Gnomad AMI AF: 0.161

Gnomad AMR AF: 0.366

Gnomad ASJ AF: 0.280

Gnomad EAS AF: 0.323

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.205

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.183

Gnomad OTH AF: 0.211

GnomAD2 exomes AF: 0.252 AC: 46012 AN: 182718 AF XY: 0.242

Gnomad AFR exome AF: 0.0287

Gnomad AMR exome AF: 0.529

Gnomad ASJ exome AF: 0.275

Gnomad EAS exome AF: 0.325

Gnomad FIN exome AF: 0.203

Gnomad NFE exome AF: 0.186

Gnomad OTH exome AF: 0.255

GnomAD4 exome AF: 0.200 AC: 216359 AN: 1079163 Hom.: 16781 Cov.: 28 AF XY: 0.204 AC XY: 70881 AN XY: 347453

African (AFR) AF: 0.0294 AC: 767 AN: 26124

American (AMR) AF: 0.508 AC: 17838 AN: 35137

Ashkenazi Jewish (ASJ) AF: 0.277 AC: 5336 AN: 19265

East Asian (EAS) AF: 0.345 AC: 10388 AN: 30125

South Asian (SAS) AF: 0.270 AC: 14471 AN: 53678

European-Finnish (FIN) AF: 0.207 AC: 8404 AN: 40507

Middle Eastern (MID) AF: 0.287 AC: 1175 AN: 4089

European-Non Finnish (NFE) AF: 0.180 AC: 148521 AN: 824759

Other (OTH) AF: 0.208 AC: 9459 AN: 45479

GnomAD4 genome AF: 0.169 AC: 18620 AN: 110342 Hom.: 1620 Cov.: 22 AF XY: 0.170 AC XY: 5527 AN XY: 32606

African (AFR) AF: 0.0312 AC: 951 AN: 30497

American (AMR) AF: 0.365 AC: 3758 AN: 10287

Ashkenazi Jewish (ASJ) AF: 0.280 AC: 733 AN: 2618

East Asian (EAS) AF: 0.324 AC: 1123 AN: 3469

South Asian (SAS) AF: 0.281 AC: 730 AN: 2602

European-Finnish (FIN) AF: 0.205 AC: 1176 AN: 5734

Middle Eastern (MID) AF: 0.307 AC: 65 AN: 212

European-Non Finnish (NFE) AF: 0.183 AC: 9662 AN: 52751

Other (OTH) AF: 0.209 AC: 314 AN: 1500

Alfa AF: 0.218 Hom.: 2827

Bravo AF: 0.182

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Kabuki syndrome 2 (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	2.8
DANN	Benign	0.47
PhyloP100		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs20539; hg19: chrX-44938563; COSMIC: COSV65037388; COSMIC: COSV65037388;