X-45089908-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001291415.2(KDM6A):c.3870T>C(p.Ala1290Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000803 in 1,206,164 control chromosomes in the GnomAD database, including 6 homozygotes. There are 266 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0043 ( 2 hom., 133 hem., cov: 22)

Exomes 𝑓: 0.00044 ( 4 hom. 133 hem. )

Consequence

KDM6A
NM_001291415.2 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.218

Publications

0 publications found

Variant links:

COSMIC-nc: COSV104429189

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP6

Variant X-45089908-T-C is Benign according to our data. Variant chrX-45089908-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 471949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.218 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00432 (481/111389) while in subpopulation AFR AF = 0.0143 (439/30641). AF 95% confidence interval is 0.0132. There are 2 homozygotes in GnomAd4. There are 133 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High AC in GnomAd4 at 481 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDM6A	NM_001291415.2 link	c.3870T>C	p.Ala1290Ala	synonymous_variant	Exon 26 of 30	ENST00000611820.5	NP_001278344.1	A0A087X0R0B7ZKN5Q86TD1B7ZKN6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KDM6A	ENST00000611820.5 link	c.3870T>C	p.Ala1290Ala	synonymous_variant	Exon 26 of 30	1	NM_001291415.2	ENSP00000483595.2		A0A087X0R0

Frequencies

GnomAD3 genomes

AF:

0.00432

AC:

481

AN:

111336

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0144

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00306

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:

0.0000188

Gnomad OTH

AF:

0.00604

GnomAD2 exomes

AF:

0.00121

AC:

219

AN:

181691

AF XY:

0.000965

show subpopulations

Gnomad AFR exome

AF:

0.0148

Gnomad AMR exome

AF:

0.000627

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000369

Gnomad OTH exome

AF:

0.000669

GnomAD4 exome

AF:

0.000445

AC:

487

AN:

1094775

Hom.:

Cov.:

AF XY:

0.000369

AC XY:

133

AN XY:

360281

show subpopulations

African (AFR)

AF:

0.0157

AC:

412

AN:

26325

American (AMR)

AF:

0.000713

AC:

AN:

35085

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19344

East Asian (EAS)

AF:

0.00

AC:

AN:

30173

South Asian (SAS)

AF:

0.0000371

AC:

AN:

53850

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40515

Middle Eastern (MID)

AF:

0.000485

AC:

AN:

4126

European-Non Finnish (NFE)

AF:

0.0000119

AC:

AN:

839391

Other (OTH)

AF:

0.000783

AC:

AN:

45966

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

105

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00432

AC:

481

AN:

111389

Hom.:

Cov.:

AF XY:

0.00396

AC XY:

133

AN XY:

33559

show subpopulations

African (AFR)

AF:

0.0143

AC:

439

AN:

30641

American (AMR)

AF:

0.00305

AC:

AN:

10477

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2642

East Asian (EAS)

AF:

0.00

AC:

AN:

3552

South Asian (SAS)

AF:

0.00

AC:

AN:

2592

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5999

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53079

Other (OTH)

AF:

0.00596

AC:

AN:

1510

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00217

Hom.:

Bravo

AF:

0.00491

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Oct 13, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Mar 19, 2019

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

KDM6A-related disorder

Benign:1

Sep 16, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

7.6

(source)

DANN

Benign

0.66

PhyloP100

-0.22

Mutation Taster

=96/4

polymorphism (auto)

(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