rs112725812

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely 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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: 4.09

Variant links:

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 links:

KDM6A (HGNC:):

KDM6A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 [Likely_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. Median coverage is 22. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KDM6A	NM_001291415.2 linkuse as main transcript	c.1999C>G	p.Leu667Val	missense_variant	17/30	ENST00000611820.5	NP_001278344.1	A0A087X0R0B7ZKN5Q86TD1B7ZKN6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KDM6A	ENST00000611820.5 linkuse as main transcript	c.1999C>G	p.Leu667Val	missense_variant	17/30	1	NM_001291415.2	ENSP00000483595.2		A0A087X0R0

Frequencies

GnomAD3 genomes

AF:

0.00654

AC:

732

AN:

111870

Hom.:

Cov.:

AF XY:

0.00538

AC XY:

183

AN XY:

34042

show subpopulations

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.:

AF XY:

0.000951

AC XY:

AN XY:

57861

show subpopulations

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.:

Cov.:

AF XY:

0.000585

AC XY:

210

AN XY:

359120

show subpopulations

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.:

Cov.:

AF XY:

0.00548

AC XY:

187

AN XY:

34104

show subpopulations

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.:

Bravo

AF:

0.00739

ESP6500AA

AF:

0.0211

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00198

AC:

240

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 15, 2020	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1Other:1

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

KDM6A-related disorder

Benign:1

Benign, no assertion criteria provided

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). -

Kabuki syndrome 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.013

.;T;.;T;T

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.74

T;T;T;T;T

MetaRNN

Benign

0.012

T;T;T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.81

.;.;.;.;L

PrimateAI

Uncertain

0.48

PROVEAN

Benign

-1.7

.;N;.;.;N

REVEL

Benign

0.072

Sift

Benign

0.033

.;D;.;.;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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over