chrX-45064935-A-G

Variant names:

• chrX-45064935-A-G
• rs6611063
• NM_001291415.2:c.2079+1118A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001291415.2(KDM6A):​c.2079+1118A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 111,321 control chromosomes in the GnomAD database, including 1,717 homozygotes. There are 6,104 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.18 (1717 hom., 6104 hem., cov: 23)
• Consequence: KDM6A NM_001291415.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.49
• 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: 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.365 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDM6A	NM_001291415.2	c.2079+1118A>G		intron_variant	Intron 17 of 29	ENST00000611820.5	NP_001278344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KDM6A	ENST00000611820.5	c.2079+1118A>G		intron_variant	Intron 17 of 29	1	NM_001291415.2	ENSP00000483595.2

Frequencies

GnomAD3 genomes AF: 0.180 AC: 20050 AN: 111269 Hom.: 1721 Cov.: 23

Gnomad AFR AF: 0.0547

Gnomad AMI AF: 0.160

Gnomad AMR AF: 0.375

Gnomad ASJ AF: 0.281

Gnomad EAS AF: 0.343

Gnomad SAS AF: 0.301

Gnomad FIN AF: 0.212

Gnomad MID AF: 0.325

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.219

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.180 AC: 20041 AN: 111321 Hom.: 1717 Cov.: 23 AF XY: 0.182 AC XY: 6104 AN XY: 33499

African (AFR) AF: 0.0545 AC: 1678 AN: 30763

American (AMR) AF: 0.375 AC: 3913 AN: 10447

Ashkenazi Jewish (ASJ) AF: 0.281 AC: 739 AN: 2634

East Asian (EAS) AF: 0.344 AC: 1215 AN: 3527

South Asian (SAS) AF: 0.300 AC: 790 AN: 2632

European-Finnish (FIN) AF: 0.212 AC: 1247 AN: 5886

Middle Eastern (MID) AF: 0.329 AC: 71 AN: 216

European-Non Finnish (NFE) AF: 0.188 AC: 9948 AN: 53022

Other (OTH) AF: 0.219 AC: 332 AN: 1519

Alfa AF: 0.182 Hom.: 1890

Bravo AF: 0.194

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	13
DANN	Benign	0.80
PhyloP100		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6611063; hg19: chrX-44924180;