chrX-45076737-T-C

Variant names:

• chrX-45076737-T-C
• rs374328447
• NM_001291415.2:c.2899T>C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4 BP6 BP7 BS2

The NM_001291415.2(KDM6A):​c.2899T>C​(p.Leu967Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,075,730 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.0000074 (0 hom. 0 hem.)
• Consequence: KDM6A NM_001291415.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.09
• Publications: 3 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.254).
• BP6: Variant X-45076737-T-C is Benign according to our data. Variant chrX-45076737-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 547393.
• BP7: Synonymous conserved (PhyloP=2.09 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 8 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM6A	NM_001291415.2	MANE Select	c.2899T>C	p.Leu967Leu	synonymous	Exon 19 of 30	NP_001278344.1
	KDM6A	NM_001419809.1		c.2899T>C	p.Leu967Leu	synonymous	Exon 19 of 31	NP_001406738.1
	KDM6A	NM_001419810.1		c.2797T>C	p.Leu933Leu	synonymous	Exon 18 of 30	NP_001406739.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM6A	ENST00000611820.5	TSL:1 MANE Select	c.2899T>C	p.Leu967Leu	synonymous	Exon 19 of 30	ENSP00000483595.2
	KDM6A	ENST00000382899.9	TSL:1	c.2764T>C	p.Leu922Leu	synonymous	Exon 18 of 29	ENSP00000372355.6
	KDM6A	ENST00000377967.9	TSL:1	c.2743T>C	p.Leu915Leu	synonymous	Exon 18 of 29	ENSP00000367203.4

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD2 exomes AF: 0.0000164 AC: 3 AN: 182924 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000731

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000744 AC: 8 AN: 1075730 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 344392

African (AFR) AF: 0.00 AC: 0 AN: 25988

American (AMR) AF: 0.0000853 AC: 3 AN: 35156

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19205

East Asian (EAS) AF: 0.00 AC: 0 AN: 30052

South Asian (SAS) AF: 0.00 AC: 0 AN: 53518

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40494

Middle Eastern (MID) AF: 0.000247 AC: 1 AN: 4044

European-Non Finnish (NFE) AF: 0.00000487 AC: 4 AN: 821900

Other (OTH) AF: 0.00 AC: 0 AN: 45373

GnomAD4 genome Cov.: 20

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Kabuki syndrome 1 Uncertain:1

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Kabuki syndrome 2 Benign:1

Sep 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	8.7
DANN	Benign	0.80
PhyloP100		2.1
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: rs374328447; hg19: chrX-44935982;