X-44873564-G-A

Variant names:

• chrX-44873564-G-A
• rs1413921299
• NM_001291415.2:c.13G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001291415.2(KDM6A):​c.13G>A​(p.Gly5Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000009 in 111,093 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: KDM6A NM_001291415.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.17

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41033953).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDM6A	NM_001291415.2	c.13G>A	p.Gly5Arg	missense_variant	Exon 1 of 30	ENST00000611820.5	NP_001278344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KDM6A	ENST00000611820.5	c.13G>A	p.Gly5Arg	missense_variant	Exon 1 of 30	1	NM_001291415.2	ENSP00000483595.2

Frequencies

GnomAD3 genomes AF: 0.00000900 AC: 1 AN: 111093 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33473

Gnomad AFR AF: 0.00

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: 0.0000190

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000183 AC: 2 AN: 1095484 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 361838

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000238

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000900 AC: 1 AN: 111093 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33473

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000190

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Kabuki syndrome 2 Uncertain:1

May 24, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.098	T;.
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Benign	0.41	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.2	L;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.9	N;.
REVEL	Uncertain	0.32
Sift	Uncertain	0.0010	D;.
Sift4G	Benign	0.16	T;T
Polyphen		0.99	D;.
Vest4		0.34
MutPred		0.34		Gain of MoRF binding (P = 0.0054);Gain of MoRF binding (P = 0.0054);
MVP		0.79
MPC		1.7
ClinPred		0.94	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.65
gMVP		0.82

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

Publications

LitVar

Other links and lift over

dbSNP: rs1413921299; hg19: chrX-44732810;