Genetic Variant KDM6A:c.-50C>G (chrX-44873502-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_001291415.2(KDM6A):c.-50C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0001 in 1,204,396 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 31 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00056 ( 0 hom., 22 hem., cov: 23)

Exomes 𝑓: 0.000054 ( 0 hom. 9 hem. )

Consequence

KDM6A
NM_001291415.2 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.27

Publications

0 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
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 (BayesDel_noAF=-0.4).

BP6

Variant X-44873502-C-G is Benign according to our data. Variant chrX-44873502-C-G is described in ClinVar as Benign. ClinVar VariationId is 1290124.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00056 (62/110632) while in subpopulation AFR AF = 0.0019 (58/30450). AF 95% confidence interval is 0.00151. There are 0 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High AC in GnomAd4 at 62 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291415.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
KDM6A	NM_001291415.2	MANE Select	c.-50C>G	5_prime_UTR	Exon 1 of 30	NP_001278344.1	A0A087X0R0
KDM6A	NM_001419809.1		c.-50C>G	5_prime_UTR	Exon 1 of 31	NP_001406738.1
KDM6A	NM_001419810.1		c.-50C>G	5_prime_UTR	Exon 1 of 30	NP_001406739.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
KDM6A	ENST00000611820.5	TSL:1 MANE Select	c.-50C>G	5_prime_UTR	Exon 1 of 30	ENSP00000483595.2	A0A087X0R0
KDM6A	ENST00000382899.9	TSL:1	c.-50C>G	5_prime_UTR	Exon 1 of 29	ENSP00000372355.6	F8W8R6
KDM6A	ENST00000377967.9	TSL:1	c.-50C>G	5_prime_UTR	Exon 1 of 29	ENSP00000367203.4	O15550

Frequencies

GnomAD3 genomes

AF:

0.000561

AC:

AN:

110579

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00191

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000377

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

GnomAD2 exomes

AF:

0.000126

AC:

AN:

175125

AF XY:

0.0000620

show subpopulations

Gnomad AFR exome

AF:

0.00180

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000137

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:

0.0000539

AC:

AN:

1093764

Hom.:

Cov.:

AF XY:

0.0000250

AC XY:

AN XY:

360298

show subpopulations

African (AFR)

AF:

0.00194

AC:

AN:

26301

American (AMR)

AF:

0.0000284

AC:

AN:

35155

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19329

East Asian (EAS)

AF:

0.00

AC:

AN:

30108

South Asian (SAS)

AF:

0.0000185

AC:

AN:

53976

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39656

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3546

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

839818

Other (OTH)

AF:

0.000131

AC:

AN:

45875

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.000560

AC:

AN:

110632

Hom.:

Cov.:

AF XY:

0.000664

AC XY:

AN XY:

33118

show subpopulations

African (AFR)

AF:

0.00190

AC:

AN:

30450

American (AMR)

AF:

0.000377

AC:

AN:

10620

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2632

East Asian (EAS)

AF:

0.00

AC:

AN:

3395

South Asian (SAS)

AF:

0.00

AC:

AN:

2645

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5914

Middle Eastern (MID)

AF:

0.00

AC:

AN:

209

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52607

Other (OTH)

AF:

0.00

AC:

AN:

1502

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

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:

0.000925

Hom.:

Bravo

AF:

0.000646

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.40

CADD

Benign

8.2

(source)

DANN

Benign

0.92

PhyloP100

1.3

PromoterAI

-0.028

Neutral

(source)

Splicing

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over