rs2230018

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001291415.2(KDM6A):c.2333C>A(p.Thr778Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,208,646 control chromosomes in the GnomAD database, including 7,744 homozygotes. There are 51,061 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 593 hom., 3326 hem., cov: 22)

Exomes 𝑓: 0.13 ( 7151 hom. 47735 hem. )

Consequence

KDM6A
NM_001291415.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: -0.985

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:

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=0.0030804276).

BP6

Variant X-45069832-C-A is Benign according to our data. Variant chrX-45069832-C-A is described in ClinVar as [Benign]. Clinvar id is 134597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.368 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KDM6A	NM_001291415.2 linkuse as main transcript	c.2333C>A	p.Thr778Lys	missense_variant	18/30	ENST00000611820.5	NP_001278344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KDM6A	ENST00000611820.5 linkuse as main transcript	c.2333C>A	p.Thr778Lys	missense_variant	18/30	1	NM_001291415.2	ENSP00000483595	P4

Frequencies

GnomAD3 genomes

AF:

0.102

AC:

11368

AN:

111179

Hom.:

595

Cov.:

AF XY:

0.0997

AC XY:

3326

AN XY:

33367

show subpopulations

Gnomad AFR

AF:

0.0429

Gnomad AMI

AF:

0.0349

Gnomad AMR

AF:

0.0514

Gnomad ASJ

AF:

0.135

Gnomad EAS

AF:

0.386

Gnomad SAS

AF:

0.185

Gnomad FIN

AF:

0.133

Gnomad MID

AF:

0.0966

Gnomad NFE

AF:

0.120

Gnomad OTH

AF:

0.0951

GnomAD3 exomes

AF:

0.134

AC:

24296

AN:

181656

Hom.:

1412

AF XY:

0.137

AC XY:

9117

AN XY:

66342

show subpopulations

Gnomad AFR exome

AF:

0.0420

Gnomad AMR exome

AF:

0.0450

Gnomad ASJ exome

AF:

0.132

Gnomad EAS exome

AF:

0.385

Gnomad SAS exome

AF:

0.199

Gnomad FIN exome

AF:

0.161

Gnomad NFE exome

AF:

0.116

Gnomad OTH exome

AF:

0.121

GnomAD4 exome

AF:

0.129

AC:

141123

AN:

1097410

Hom.:

7151

Cov.:

AF XY:

0.132

AC XY:

47735

AN XY:

362846

show subpopulations

Gnomad4 AFR exome

AF:

0.0405

Gnomad4 AMR exome

AF:

0.0443

Gnomad4 ASJ exome

AF:

0.133

Gnomad4 EAS exome

AF:

0.428

Gnomad4 SAS exome

AF:

0.191

Gnomad4 FIN exome

AF:

0.164

Gnomad4 NFE exome

AF:

0.118

Gnomad4 OTH exome

AF:

0.131

GnomAD4 genome

AF:

0.102

AC:

11367

AN:

111236

Hom.:

593

Cov.:

AF XY:

0.0995

AC XY:

3326

AN XY:

33434

show subpopulations

Gnomad4 AFR

AF:

0.0428

Gnomad4 AMR

AF:

0.0513

Gnomad4 ASJ

AF:

0.135

Gnomad4 EAS

AF:

0.385

Gnomad4 SAS

AF:

0.184

Gnomad4 FIN

AF:

0.133

Gnomad4 NFE

AF:

0.120

Gnomad4 OTH

AF:

0.100

Alfa

AF:

0.119

Hom.:

9719

Bravo

AF:

0.0944

TwinsUK

AF:

0.120

AC:

445

ALSPAC

AF:

0.115

AC:

333

ESP6500AA

AF:

0.0485

AC:

186

ESP6500EA

AF:

0.118

AC:

794

ExAC

AF:

0.136

AC:

16555

ClinVar

Significance: Benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3Other:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 29, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 01, 2013	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Kabuki syndrome 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.028

DANN

Benign

0.85

DEOGEN2

Benign

0.031

.;T;.;T;T

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.48

T;T;T;T;T

MetaRNN

Benign

0.0031

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

.;.;.;.;N

MutationTaster

Benign

1.0

P;P;P;P

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.2

.;.;.;.;N

REVEL

Benign

0.058

Sift

Benign

0.056

.;.;.;.;T

Sift4G

Benign

0.69

T;T;T;T;T

Polyphen

0.046

.;.;.;.;B

Vest4

0.077

MPC

0.13

ClinPred

0.0066

GERP RS

-2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.23

gMVP

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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