rs5952285

Variant names:

• chrX-45053807-T-A
• rs5952285
• NM_001291415.2:c.749-22T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000611820.5(KDM6A):​c.749-22T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0921 in 1,152,765 control chromosomes in the GnomAD database, including 9,819 homozygotes. There are 31,772 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4347 hom., 6876 hem., cov: 22)
  • Exomes 𝑓: 0.078 (5472 hom. 24896 hem.)
• Consequence: KDM6A ENST00000611820.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.64
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant X-45053807-T-A is Benign according to our data. Variant chrX-45053807-T-A is described in ClinVar as Benign. ClinVar VariationId is 1222327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.601 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.749-22T>A		intron	N/A	NP_001278344.1
	KDM6A	NM_001419809.1		c.749-22T>A		intron	N/A	NP_001406738.1
	KDM6A	NM_001419810.1		c.749-22T>A		intron	N/A	NP_001406739.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM6A	ENST00000611820.5	TSL:1 MANE Select	c.749-22T>A		intron	N/A	ENSP00000483595.2
	KDM6A	ENST00000382899.9	TSL:1	c.749-22T>A		intron	N/A	ENSP00000372355.6
	KDM6A	ENST00000377967.9	TSL:1	c.749-22T>A		intron	N/A	ENSP00000367203.4

Frequencies

GnomAD3 genomes AF: 0.219 AC: 24412 AN: 111426 Hom.: 4336 Cov.: 22

Gnomad AFR AF: 0.608

Gnomad AMI AF: 0.0368

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.0659

Gnomad EAS AF: 0.0479

Gnomad SAS AF: 0.137

Gnomad FIN AF: 0.0313

Gnomad MID AF: 0.143

Gnomad NFE AF: 0.0659

Gnomad OTH AF: 0.189

GnomAD2 exomes AF: 0.106 AC: 19044 AN: 179523 AF XY: 0.0938

Gnomad AFR exome AF: 0.615

Gnomad AMR exome AF: 0.0600

Gnomad ASJ exome AF: 0.0702

Gnomad EAS exome AF: 0.0497

Gnomad FIN exome AF: 0.0328

Gnomad NFE exome AF: 0.0620

Gnomad OTH exome AF: 0.0847

GnomAD4 exome AF: 0.0785 AC: 81716 AN: 1041288 Hom.: 5472 Cov.: 22 AF XY: 0.0777 AC XY: 24896 AN XY: 320434

African (AFR) AF: 0.625 AC: 15610 AN: 24957

American (AMR) AF: 0.0661 AC: 2314 AN: 35029

Ashkenazi Jewish (ASJ) AF: 0.0672 AC: 1275 AN: 18984

East Asian (EAS) AF: 0.0311 AC: 929 AN: 29908

South Asian (SAS) AF: 0.131 AC: 6894 AN: 52553

European-Finnish (FIN) AF: 0.0326 AC: 1319 AN: 40434

Middle Eastern (MID) AF: 0.123 AC: 490 AN: 3972

European-Non Finnish (NFE) AF: 0.0611 AC: 48322 AN: 791248

Other (OTH) AF: 0.103 AC: 4563 AN: 44203

GnomAD4 genome AF: 0.219 AC: 24461 AN: 111477 Hom.: 4347 Cov.: 22 AF XY: 0.204 AC XY: 6876 AN XY: 33727

African (AFR) AF: 0.609 AC: 18542 AN: 30468

American (AMR) AF: 0.112 AC: 1177 AN: 10554

Ashkenazi Jewish (ASJ) AF: 0.0659 AC: 174 AN: 2641

East Asian (EAS) AF: 0.0472 AC: 168 AN: 3560

South Asian (SAS) AF: 0.136 AC: 366 AN: 2683

European-Finnish (FIN) AF: 0.0313 AC: 189 AN: 6033

Middle Eastern (MID) AF: 0.148 AC: 32 AN: 216

European-Non Finnish (NFE) AF: 0.0659 AC: 3502 AN: 53127

Other (OTH) AF: 0.189 AC: 286 AN: 1515

Alfa AF: 0.141 Hom.: 1323

Bravo AF: 0.242

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	4.6
DANN	Benign	0.53
PhyloP100		1.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs5952285; hg19: chrX-44913052; COSMIC: COSV65037565;