rs1373790479

Positions:

• chrX-44961308-A-G
• chrX-44961308-A-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001291415.2(KDM6A):​c.250A>G​(p.Ile84Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000734 in 1,090,607 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes 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., 1 hem., cov: 23)
  • Exomes 𝑓: 0.0000073 (0 hom. 2 hem.)
  • Failed GnomAD Quality Control
• Consequence: KDM6A NM_001291415.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:2
• Conservation: PhyloP100: 8.70

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3136741).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KDM6A	NM_001291415.2	c.250A>G	p.Ile84Val	missense_variant	3/30	ENST00000611820.5	NP_001278344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KDM6A	ENST00000611820.5	c.250A>G	p.Ile84Val	missense_variant	3/30	1	NM_001291415.2	ENSP00000483595	P4

Frequencies

GnomAD3 genomes AF: 0.00000895 AC: 1 AN: 111685 Hom.: 0 Cov.: 23 AF XY: 0.0000295 AC XY: 1 AN XY: 33899

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: 0.0000189

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000734 AC: 8 AN: 1090607 Hom.: 0 Cov.: 27 AF XY: 0.00000560 AC XY: 2 AN XY: 357241

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: 0.00000956

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000895 AC: 1 AN: 111685 Hom.: 0 Cov.: 23 AF XY: 0.0000295 AC XY: 1 AN XY: 33899

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: 0.0000189

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Kabuki syndrome 2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 12, 2023	Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KDM6A protein function. ClinVar contains an entry for this variant (Variation ID: 488374). This variant has not been reported in the literature in individuals affected with KDM6A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 84 of the KDM6A protein (p.Ile84Val). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	research	Sbielas Lab-Department of Human Genetics University of Michigan, University of Michigan Medical School	Oct 27, 2017	- -

CHARGE syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.020	.;T;.;T;T;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T;T;T;T;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.31	T;T;T;T;T;T
MetaSVM	Uncertain	0.019	D
MutationAssessor	Uncertain	2.2	.;.;.;.;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.91	.;.;.;.;N;.
REVEL	Benign	0.22
Sift	Benign	0.062	.;.;.;.;T;.
Sift4G	Benign	0.28	T;T;T;T;T;T
Polyphen		0.39	.;.;.;.;B;.
Vest4		0.32
MutPred		0.36		.;.;.;.;Gain of ubiquitination at K86 (P = 0.1378);Gain of ubiquitination at K86 (P = 0.1378);
MVP		0.62
MPC		0.81
ClinPred		0.86	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.22

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: rs1373790479; hg19: chrX-44820553;