rs112725812

chrX-45063737-C-GchrX-45063737-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001291415.2(KDM6A):c.1999C>G(p.Leu667Val) variant causes a missense change. The variant allele was found at a frequency of 0.00136 in 1,205,284 control chromosomes in the GnomAD database, including 13 homozygotes. There are 397 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (6 hom., 187 hem., cov: 22)
  • Exomes 𝑓: 0.00082 (7 hom. 210 hem.)
• Consequence: KDM6A NM_001291415.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 4.09

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012268305).
• BP6: Variant X-45063737-C-G is Benign according to our data. Variant chrX-45063737-C-G is described in ClinVar as [Benign]. Clinvar id is 134596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00658 (736/111922) while in subpopulation AFR AF= 0.0231 (711/30741). AF 95% confidence interval is 0.0217. There are 6 homozygotes in gnomad4. There are 187 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KDM6A	NM_001291415.2	c.1999C>G	p.Leu667Val	missense_variant	17/30	ENST00000611820.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KDM6A	ENST00000611820.5	c.1999C>G	p.Leu667Val	missense_variant	17/30	1	NM_001291415.2	P4

Frequencies

GnomAD3 genomes AF: 0.00654 AC: 732 AN: 111870 Hom.: 6 Cov.: 22 AF XY: 0.00538 AC XY: 183 AN XY: 34042

Gnomad AFR AF: 0.0230

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00152

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: 0.0000564

Gnomad OTH AF: 0.00399

GnomAD3 exomes AF: 0.00184 AC: 317 AN: 172315 Hom.: 1 AF XY: 0.000951 AC XY: 55 AN XY: 57861

Gnomad AFR exome AF: 0.0231

Gnomad AMR exome AF: 0.000943

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000568

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000132

Gnomad OTH exome AF: 0.000461

GnomAD4 exome AF: 0.000822 AC: 899 AN: 1093362 Hom.: 7 Cov.: 30 AF XY: 0.000585 AC XY: 210 AN XY: 359120

Gnomad4 AFR exome AF: 0.0253

Gnomad4 AMR exome AF: 0.00106

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000749

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000119

Gnomad4 OTH exome AF: 0.00176

GnomAD4 genome AF: 0.00658 AC: 736 AN: 111922 Hom.: 6 Cov.: 22 AF XY: 0.00548 AC XY: 187 AN XY: 34104

Gnomad4 AFR AF: 0.0231

Gnomad4 AMR AF: 0.00151

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000564

Gnomad4 OTH AF: 0.00394

Alfa AF: 0.00269 Hom.: 10

Bravo AF: 0.00739

ESP6500AA AF: 0.0211 AC: 81

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00198 AC: 240

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 07, 2018	- -

KDM6A-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 14, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 15, 2020

- -

Kabuki syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	20
Dann	Benign	0.96
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.74	T;T;T;T;T
MetaRNN	Benign	0.012	T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationTaster	Benign	0.0082	P;P;P;P
PrimateAI	Uncertain	0.48	T
Sift4G	Benign	0.52	T;T;T;T;T
Polyphen		0.020	.;.;.;.;B
Vest4		0.19
MVP		0.38
MPC		0.11
ClinPred		0.0081	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.087
gMVP		0.43

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: rs112725812; hg19: chrX-44922982;