X-45076679-C-CT

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001291415.2(KDM6A):​c.2859-5dupT 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (11 hom., 117 hem., cov: 0)
  • Exomes 𝑓: 0.0013 (0 hom. 28 hem.)
• Consequence: KDM6A NM_001291415.2 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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 -16 ACMG points.

• BP6: Variant X-45076679-C-CT is Benign according to our data. Variant chrX-45076679-C-CT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1166903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00879 (777/88386) while in subpopulation AFR AF = 0.0304 (749/24632). AF 95% confidence interval is 0.0286. There are 11 homozygotes in GnomAd4. There are 117 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 777 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.2859-5dupT		splice_region intron	N/A	NP_001278344.1	A0A087X0R0
	KDM6A	NM_001419809.1		c.2859-5dupT		splice_region intron	N/A	NP_001406738.1
	KDM6A	NM_001419810.1		c.2757-5dupT		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.2859-5dupT		splice_region intron	N/A	ENSP00000483595.2	A0A087X0R0
	KDM6A	ENST00000382899.9	TSL:1	c.2724-5dupT		splice_region intron	N/A	ENSP00000372355.6	F8W8R6
	KDM6A	ENST00000377967.9	TSL:1	c.2703-5dupT		splice_region intron	N/A	ENSP00000367203.4	O15550

Frequencies

GnomAD3 genomes AF: 0.00873 AC: 772 AN: 88381 Hom.: 10 Cov.: 0

Gnomad AFR AF: 0.0302

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00227

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000667

Gnomad OTH AF: 0.00701

GnomAD2 exomes AF: 0.00427 AC: 339 AN: 79362 AF XY: 0.000429

Gnomad AFR exome AF: 0.0406

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000138

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000237

Gnomad OTH exome AF: 0.00102

GnomAD4 exome AF: 0.00125 AC: 916 AN: 732188 Hom.: 0 Cov.: 0 AF XY: 0.000133 AC XY: 28 AN XY: 210298

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0324 AC: 620 AN: 19108

American (AMR) AF: 0.00136 AC: 35 AN: 25660

Ashkenazi Jewish (ASJ) AF: 0.0000711 AC: 1 AN: 14074

East Asian (EAS) AF: 0.000649 AC: 16 AN: 24668

South Asian (SAS) AF: 0.000102 AC: 4 AN: 39145

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32650

Middle Eastern (MID) AF: 0.00463 AC: 14 AN: 3024

European-Non Finnish (NFE) AF: 0.000253 AC: 137 AN: 541876

Other (OTH) AF: 0.00278 AC: 89 AN: 31983

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00879 AC: 777 AN: 88386 Hom.: 11 Cov.: 0 AF XY: 0.00696 AC XY: 117 AN XY: 16802

African (AFR) AF: 0.0304 AC: 749 AN: 24632

American (AMR) AF: 0.00226 AC: 17 AN: 7513

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2258

East Asian (EAS) AF: 0.00 AC: 0 AN: 2889

South Asian (SAS) AF: 0.00 AC: 0 AN: 1672

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2527

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 175

European-Non Finnish (NFE) AF: 0.0000667 AC: 3 AN: 44993

Other (OTH) AF: 0.00692 AC: 8 AN: 1156

Alfa AF: 0.00118 Hom.: 1920

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.70
Mutation Taster		=100/0	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs10605935; hg19: chrX-44935924;