chrX-45076679-CT-C

Variant names:

• chrX-45076679-CT-C
• rs10605935
• NM_001291415.2:c.2859-5delT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_001291415.2(KDM6A):​c.2859-5delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (22303 hom., 12450 hem., cov: 0)
  • Exomes 𝑓: 0.57 (38906 hom. 46201 hem.)
  • Failed GnomAD Quality Control
• Consequence: KDM6A NM_001291415.2 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.699
• 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• Kabuki syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP6: Variant X-45076679-CT-C is Benign according to our data. Variant chrX-45076679-CT-C is described in ClinVar as Benign. ClinVar VariationId is 281158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2859-5delT		splice_region intron	N/A	NP_001278344.1	A0A087X0R0
	KDM6A	NM_001419809.1		c.2859-5delT		splice_region intron	N/A	NP_001406738.1
	KDM6A	NM_001419810.1		c.2757-5delT		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.2859-5delT		splice_region intron	N/A	ENSP00000483595.2	A0A087X0R0
	KDM6A	ENST00000382899.9	TSL:1	c.2724-5delT		splice_region intron	N/A	ENSP00000372355.6	F8W8R6
	KDM6A	ENST00000377967.9	TSL:1	c.2703-5delT		splice_region intron	N/A	ENSP00000367203.4	O15550

Frequencies

GnomAD3 genomes AF: 0.775 AC: 68346 AN: 88152 Hom.: 22316 Cov.: 0

Gnomad AFR AF: 0.588

Gnomad AMI AF: 0.961

Gnomad AMR AF: 0.887

Gnomad ASJ AF: 0.852

Gnomad EAS AF: 0.615

Gnomad SAS AF: 0.730

Gnomad FIN AF: 0.794

Gnomad MID AF: 0.870

Gnomad NFE AF: 0.863

Gnomad OTH AF: 0.798

GnomAD2 exomes AF: 0.532 AC: 42237 AN: 79362 AF XY: 0.663

Gnomad AFR exome AF: 0.473

Gnomad AMR exome AF: 0.549

Gnomad ASJ exome AF: 0.534

Gnomad EAS exome AF: 0.474

Gnomad FIN exome AF: 0.560

Gnomad NFE exome AF: 0.552

Gnomad OTH exome AF: 0.531

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.565 AC: 337605 AN: 597170 Hom.: 38906 Cov.: 0 AF XY: 0.602 AC XY: 46201 AN XY: 76766

African (AFR) AF: 0.441 AC: 7503 AN: 17030

American (AMR) AF: 0.549 AC: 11446 AN: 20836

Ashkenazi Jewish (ASJ) AF: 0.542 AC: 5945 AN: 10971

East Asian (EAS) AF: 0.421 AC: 8763 AN: 20826

South Asian (SAS) AF: 0.462 AC: 11281 AN: 24404

European-Finnish (FIN) AF: 0.529 AC: 13934 AN: 26317

Middle Eastern (MID) AF: 0.638 AC: 1559 AN: 2442

European-Non Finnish (NFE) AF: 0.586 AC: 262667 AN: 447938

Other (OTH) AF: 0.549 AC: 14507 AN: 26406

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.775 AC: 68334 AN: 88156 Hom.: 22303 Cov.: 0 AF XY: 0.748 AC XY: 12450 AN XY: 16642

African (AFR) AF: 0.588 AC: 14449 AN: 24588

American (AMR) AF: 0.887 AC: 6646 AN: 7495

Ashkenazi Jewish (ASJ) AF: 0.852 AC: 1916 AN: 2249

East Asian (EAS) AF: 0.614 AC: 1771 AN: 2883

South Asian (SAS) AF: 0.730 AC: 1215 AN: 1664

European-Finnish (FIN) AF: 0.794 AC: 1998 AN: 2516

Middle Eastern (MID) AF: 0.891 AC: 156 AN: 175

European-Non Finnish (NFE) AF: 0.863 AC: 38722 AN: 44864

Other (OTH) AF: 0.793 AC: 916 AN: 1155

Alfa AF: 0.549 Hom.: 1920

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Kabuki syndrome 2 (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.70
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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; COSMIC: COSV65048100;