X-45076679-CTTTT-CTTTTTT

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_001291415.2(KDM6A):​c.2859-6_2859-5dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.000023 (0 hom., 0 hem., cov: 0)
  • Exomes 𝑓: 0.000024 (0 hom. 0 hem.)
• Consequence: KDM6A NM_001291415.2 splice_region, intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• 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: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant X-45076679-C-CTT is Benign according to our data. Variant chrX-45076679-C-CTT is described in ClinVar as Likely_benign. ClinVar VariationId is 3352588.Status of the report is no_assertion_criteria_provided, 0 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.2859-6_2859-5dupTT		splice_region intron	N/A	NP_001278344.1	A0A087X0R0
	KDM6A	NM_001419809.1		c.2859-6_2859-5dupTT		splice_region intron	N/A	NP_001406738.1
	KDM6A	NM_001419810.1		c.2757-6_2757-5dupTT		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_2859-5dupTT		splice_region intron	N/A	ENSP00000483595.2	A0A087X0R0
	KDM6A	ENST00000382899.9	TSL:1	c.2724-6_2724-5dupTT		splice_region intron	N/A	ENSP00000372355.6	F8W8R6
	KDM6A	ENST00000377967.9	TSL:1	c.2703-6_2703-5dupTT		splice_region intron	N/A	ENSP00000367203.4	O15550

Frequencies

GnomAD3 genomes AF: 0.0000226 AC: 2 AN: 88389 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000813

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000378 AC: 3 AN: 79362 AF XY: 0.00

Gnomad AFR exome AF: 0.000390

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000245 AC: 18 AN: 735337 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 211871

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

African (AFR) AF: 0.000662 AC: 13 AN: 19646

American (AMR) AF: 0.0000388 AC: 1 AN: 25762

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14105

East Asian (EAS) AF: 0.00 AC: 0 AN: 24732

South Asian (SAS) AF: 0.00 AC: 0 AN: 39331

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32689

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3029

European-Non Finnish (NFE) AF: 0.00000552 AC: 3 AN: 543887

Other (OTH) AF: 0.0000311 AC: 1 AN: 32156

⚠️ 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: 0.0000226 AC: 2 AN: 88389 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 16785

African (AFR) AF: 0.0000813 AC: 2 AN: 24607

American (AMR) AF: 0.00 AC: 0 AN: 7503

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 2902

South Asian (SAS) AF: 0.00 AC: 0 AN: 1688

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 192

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 45000

Other (OTH) AF: 0.00 AC: 0 AN: 1141

Alfa AF: 0.00 Hom.: 1920

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	KDM6A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.70

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10605935; hg19: chrX-44935924;