X-45076726-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_ModerateBP6_ModerateBS1BS2

The NM_001291415.2(KDM6A):c.2888G>C(p.Ser963Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000501 in 1,157,800 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 27 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.000041 ( 0 hom., 1 hem., cov: 20)

Exomes 𝑓: 0.000051 ( 0 hom. 26 hem. )

Consequence

KDM6A
NM_001291415.2 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2O:1

Conservation

PhyloP100: 6.39

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

Kabuki syndrome 2
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
Kabuki syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

KDM6A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10689333).

BP6

Variant X-45076726-G-C is Benign according to our data. Variant chrX-45076726-G-C is described in ClinVar as Benign. ClinVar VariationId is 134598.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000408 (4/97981) while in subpopulation SAS AF = 0.000961 (2/2082). AF 95% confidence interval is 0.00017. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 54 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDM6A	NM_001291415.2 link	c.2888G>C	p.Ser963Thr	missense_variant	Exon 19 of 30	ENST00000611820.5	NP_001278344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KDM6A	ENST00000611820.5 link	c.2888G>C	p.Ser963Thr	missense_variant	Exon 19 of 30	1	NM_001291415.2	ENSP00000483595.2

Frequencies

GnomAD3 genomes

AF:

0.0000408

AC:

AN:

97949

Hom.:

Cov.:

show subpopulations

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:

0.000955

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000403

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000659

AC:

AN:

181991

AF XY:

0.000105

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000510

AC:

AN:

1059819

Hom.:

Cov.:

AF XY:

0.0000780

AC XY:

AN XY:

333487

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25554

American (AMR)

AF:

0.00

AC:

AN:

34811

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18910

East Asian (EAS)

AF:

0.00

AC:

AN:

29621

South Asian (SAS)

AF:

0.000397

AC:

AN:

52903

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40145

Middle Eastern (MID)

AF:

0.00150

AC:

AN:

3991

European-Non Finnish (NFE)

AF:

0.0000309

AC:

AN:

809293

Other (OTH)

AF:

0.0000449

AC:

AN:

44591

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000408

AC:

AN:

97981

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

24767

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26056

American (AMR)

AF:

0.00

AC:

AN:

8262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2506

East Asian (EAS)

AF:

0.00

AC:

AN:

3196

South Asian (SAS)

AF:

0.000961

AC:

AN:

2082

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4143

Middle Eastern (MID)

AF:

0.00

AC:

AN:

161

European-Non Finnish (NFE)

AF:

0.0000403

AC:

AN:

49663

Other (OTH)

AF:

0.00

AC:

AN:

1265

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.592

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

KDM6A-related disorder

Benign:1

Sep 14, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely 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

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.024

.;T;.;T;T

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;D;D;D;D

M_CAP

Pathogenic

0.65

MetaRNN

Benign

0.11

T;T;T;T;T

MetaSVM

Uncertain

0.27

MutationAssessor

Benign

1.9

.;.;.;.;L

PhyloP100

6.4

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-2.1

.;.;.;.;N

REVEL

Uncertain

0.41

Sift

Benign

0.14

.;.;.;.;T

Sift4G

Benign

0.44

T;T;T;T;T

Polyphen

0.86

.;.;.;.;P

Vest4

0.15

MVP

0.71

MPC

0.10

ClinPred

0.15

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.79

gMVP

0.29

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over