X-44873575-C-T

Variant names:

• chrX-44873575-C-T
• rs2031055969
• NM_001291415.2:c.24C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001291421.2(KDM6A):​c.-609C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000915 in 1,092,398 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: KDM6A NM_001291421.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.27
• Publications: 0 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant X-44873575-C-T is Benign according to our data. Variant chrX-44873575-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 932490.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291421.2. 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.24C>T	p.Leu8Leu	synonymous	Exon 1 of 30	NP_001278344.1	A0A087X0R0
	KDM6A	NM_001291421.2		c.-609C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 27	NP_001278350.1
	KDM6A	NM_001419809.1		c.24C>T	p.Leu8Leu	synonymous	Exon 1 of 31	NP_001406738.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM6A	ENST00000611820.5	TSL:1 MANE Select	c.24C>T	p.Leu8Leu	synonymous	Exon 1 of 30	ENSP00000483595.2	A0A087X0R0
	KDM6A	ENST00000382899.9	TSL:1	c.24C>T	p.Leu8Leu	synonymous	Exon 1 of 29	ENSP00000372355.6	F8W8R6
	KDM6A	ENST00000377967.9	TSL:1	c.24C>T	p.Leu8Leu	synonymous	Exon 1 of 29	ENSP00000367203.4	O15550

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.15e-7 AC: 1 AN: 1092398 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 359662

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

African (AFR) AF: 0.00 AC: 0 AN: 26338

American (AMR) AF: 0.00 AC: 0 AN: 34760

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19279

East Asian (EAS) AF: 0.00 AC: 0 AN: 29988

South Asian (SAS) AF: 0.00 AC: 0 AN: 53649

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38686

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3994

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 839964

Other (OTH) AF: 0.0000219 AC: 1 AN: 45740

⚠️ 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 Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	11
DANN	Uncertain	0.98
PhyloP100		2.3
PromoterAI		-0.0092	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs2031055969; hg19: chrX-44732821;