X-45069832-C-T

Position:

chrX-45069832-C-T

Variant summary

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

The NM_001291415.2(KDM6A):c.2333C>T(p.Thr778Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000256 in 1,208,747 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 114 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., 5 hem., cov: 22)

Exomes 𝑓: 0.00026 ( 0 hom. 109 hem. )

Consequence

KDM6A
NM_001291415.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

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:

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=0.03868887).

BP6

Variant X-45069832-C-T is Benign according to our data. Variant chrX-45069832-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 379452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000198 (22/111262) while in subpopulation SAS AF= 0.000764 (2/2618). AF 95% confidence interval is 0.000204. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KDM6A	NM_001291415.2 linkuse as main transcript	c.2333C>T	p.Thr778Met	missense_variant	18/30	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.2333C>T	p.Thr778Met	missense_variant	18/30	1	NM_001291415.2	ENSP00000483595.2		A0A087X0R0

Frequencies

GnomAD3 genomes

AF:

0.000198

AC:

AN:

111205

Hom.:

Cov.:

AF XY:

0.000150

AC XY:

AN XY:

33377

show subpopulations

Gnomad AFR

AF:

0.0000327

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000953

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000762

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000321

Gnomad OTH

AF:

0.000669

GnomAD3 exomes

AF:

0.000220

AC:

AN:

181656

Hom.:

AF XY:

0.000256

AC XY:

AN XY:

66342

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000220

Gnomad ASJ exome

AF:

0.000134

Gnomad EAS exome

AF:

0.000146

Gnomad SAS exome

AF:

0.000528

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000186

Gnomad OTH exome

AF:

0.00134

GnomAD4 exome

AF:

0.000262

AC:

287

AN:

1097485

Hom.:

Cov.:

AF XY:

0.000300

AC XY:

109

AN XY:

362879

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000341

Gnomad4 ASJ exome

AF:

0.0000516

Gnomad4 EAS exome

AF:

0.0000994

Gnomad4 SAS exome

AF:

0.000481

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000269

Gnomad4 OTH exome

AF:

0.000304

GnomAD4 genome

AF:

0.000198

AC:

AN:

111262

Hom.:

Cov.:

AF XY:

0.000150

AC XY:

AN XY:

33444

show subpopulations

Gnomad4 AFR

AF:

0.0000326

Gnomad4 AMR

AF:

0.0000952

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000764

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000321

Gnomad4 OTH

AF:

0.000660

Alfa

AF:

0.0000128

Hom.:

9719

Bravo

AF:

0.000208

ExAC

AF:

0.000181

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 23, 2015

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2023

KDM6A: BP4, BS2 -

Kabuki syndrome 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.018

DANN

Benign

0.84

DEOGEN2

Benign

0.015

.;T;.;T;T

FATHMM_MKL

Benign

0.078

LIST_S2

Uncertain

0.86

D;D;D;D;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.039

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

.;.;.;.;N

MutationTaster

Benign

1.0

P;P;P;P

PrimateAI

Benign

0.24

PROVEAN

Benign

0.81

.;.;.;.;N

REVEL

Benign

0.062

Sift

Benign

0.14

.;.;.;.;T

Sift4G

Benign

0.090

T;T;T;T;T

Polyphen

0.65

.;.;.;.;P

Vest4

0.052

MVP

0.19

MPC

0.11

ClinPred

0.0066

GERP RS

-2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.041

gMVP

0.25

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