rs141303384

Positions:

chrX-45082610-A-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.3335A>T(p.His1112Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000138 in 1,192,328 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 36 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. H1112H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00072 ( 0 hom., 19 hem., cov: 23)

Exomes 𝑓: 0.000078 ( 0 hom. 17 hem. )

Consequence

KDM6A
NM_001291415.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: 8.09

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:

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=0.007758707).

BP6

Variant X-45082610-A-T is Benign according to our data. Variant chrX-45082610-A-T is described in ClinVar as [Benign]. Clinvar id is 134599.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 = 0.000718 (80/111427) while in subpopulation AFR AF= 0.00258 (79/30662). AF 95% confidence interval is 0.00212. There are 0 homozygotes in gnomad4. There are 19 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 19 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KDM6A	NM_001291415.2 linkuse as main transcript	c.3335A>T	p.His1112Leu	missense_variant	22/30	ENST00000611820.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KDM6A	ENST00000611820.5 linkuse as main transcript	c.3335A>T	p.His1112Leu	missense_variant	22/30	1	NM_001291415.2	P4

Frequencies

GnomAD3 genomes

AF:

0.000718

AC:

AN:

111379

Hom.:

Cov.:

AF XY:

0.000566

AC XY:

AN XY:

33567

show subpopulations

Gnomad AFR

AF:

0.00258

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000954

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000262

AC:

AN:

183201

Hom.:

AF XY:

0.000162

AC XY:

AN XY:

67699

show subpopulations

Gnomad AFR exome

AF:

0.00350

Gnomad AMR exome

AF:

0.0000730

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.0000777

AC:

AN:

1080901

Hom.:

Cov.:

AF XY:

0.0000488

AC XY:

AN XY:

348469

show subpopulations

Gnomad4 AFR exome

AF:

0.00296

Gnomad4 AMR exome

AF:

0.000142

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000440

GnomAD4 genome

AF:

0.000718

AC:

AN:

111427

Hom.:

Cov.:

AF XY:

0.000565

AC XY:

AN XY:

33625

show subpopulations

Gnomad4 AFR

AF:

0.00258

Gnomad4 AMR

AF:

0.0000952

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000189

Hom.:

Bravo

AF:

0.000774

ESP6500AA

AF:

0.00339

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000346

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 17, 2015	- -

Kabuki syndrome 2;CN030661:Kabuki syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 13, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 25, 2019

- -

Kabuki syndrome 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.053

.;T;.;T;T

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.81

T;T;T;T;T

M_CAP

Pathogenic

0.31

MetaRNN

Benign

0.0078

T;T;T;T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.90

.;.;.;.;L

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-4.0

.;.;.;.;D

REVEL

Uncertain

0.44

Sift

Benign

0.67

.;.;.;.;T

Sift4G

Benign

0.66

T;T;T;T;T

Polyphen

0.0010

.;.;.;.;B

Vest4

0.50

MVP

0.81

MPC

0.92

ClinPred

0.090

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.61

gMVP

0.33

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