X-45076679-CTT-C

Variant names:

• chrX-45076679-CTT-C
• rs10605935
• NM_001291415.2:c.2859-6_2859-5delTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001419809.1(KDM6A):​c.2859-6_2859-5delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.223 in 685,890 control chromosomes in the GnomAD database, including 3,708 homozygotes. There are 20,772 hemizygotes in GnomAD. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (635 hom., 2188 hem., cov: 0)
  • Exomes 𝑓: 0.24 (3073 hom. 18584 hem.)
• Consequence: KDM6A NM_001419809.1 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.198
• Publications: 5 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 -16 ACMG points.

• BP6: Variant X-45076679-CTT-C is Benign according to our data. Variant chrX-45076679-CTT-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 167213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.36 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001419809.1. 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.2859-6_2859-5delTT		splice_region intron	N/A	NP_001278344.1
	KDM6A	NM_001419809.1		c.2859-6_2859-5delTT		splice_region intron	N/A	NP_001406738.1
	KDM6A	NM_001419810.1		c.2757-6_2757-5delTT		splice_region intron	N/A	NP_001406739.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM6A	ENST00000611820.5	TSL:1 MANE Select	c.2859-6_2859-5delTT		splice_region intron	N/A	ENSP00000483595.2
	KDM6A	ENST00000382899.9	TSL:1	c.2724-6_2724-5delTT		splice_region intron	N/A	ENSP00000372355.6
	KDM6A	ENST00000377967.9	TSL:1	c.2703-6_2703-5delTT		splice_region intron	N/A	ENSP00000367203.4

Frequencies

GnomAD3 genomes AF: 0.123 AC: 10866 AN: 88221 Hom.: 635 Cov.: 0

Gnomad AFR AF: 0.0761

Gnomad AMI AF: 0.0403

Gnomad AMR AF: 0.0686

Gnomad ASJ AF: 0.146

Gnomad EAS AF: 0.378

Gnomad SAS AF: 0.265

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.122

GnomAD2 exomes AF: 0.329 AC: 26110 AN: 79362 AF XY: 0.331

Gnomad AFR exome AF: 0.161

Gnomad AMR exome AF: 0.271

Gnomad ASJ exome AF: 0.343

Gnomad EAS exome AF: 0.435

Gnomad FIN exome AF: 0.360

Gnomad NFE exome AF: 0.344

Gnomad OTH exome AF: 0.312

GnomAD4 exome AF: 0.237 AC: 141928 AN: 597667 Hom.: 3073 AF XY: 0.140 AC XY: 18584 AN XY: 132807

African (AFR) AF: 0.117 AC: 2084 AN: 17758

American (AMR) AF: 0.219 AC: 4254 AN: 19400

Ashkenazi Jewish (ASJ) AF: 0.264 AC: 2793 AN: 10593

East Asian (EAS) AF: 0.440 AC: 8881 AN: 20200

South Asian (SAS) AF: 0.281 AC: 8013 AN: 28525

European-Finnish (FIN) AF: 0.306 AC: 7238 AN: 23652

Middle Eastern (MID) AF: 0.205 AC: 488 AN: 2379

European-Non Finnish (NFE) AF: 0.227 AC: 101906 AN: 449011

Other (OTH) AF: 0.240 AC: 6271 AN: 26149

GnomAD4 genome AF: 0.123 AC: 10866 AN: 88223 Hom.: 635 Cov.: 0 AF XY: 0.131 AC XY: 2188 AN XY: 16727

African (AFR) AF: 0.0762 AC: 1874 AN: 24604

American (AMR) AF: 0.0685 AC: 514 AN: 7499

Ashkenazi Jewish (ASJ) AF: 0.146 AC: 330 AN: 2254

East Asian (EAS) AF: 0.378 AC: 1091 AN: 2884

South Asian (SAS) AF: 0.266 AC: 444 AN: 1670

European-Finnish (FIN) AF: 0.183 AC: 462 AN: 2520

Middle Eastern (MID) AF: 0.0857 AC: 15 AN: 175

European-Non Finnish (NFE) AF: 0.133 AC: 5965 AN: 44892

Other (OTH) AF: 0.128 AC: 148 AN: 1154

Alfa AF: 0.198 Hom.: 1920

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.20
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs10605935; hg19: chrX-44935924;