Genetic Variant KDM6A:c.-176_-165dupGCCGCCGCCGCC (chrX-44873369-T-TGCCGCCGCCGCC) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001291415.2(KDM6A):c.-176_-165dupGCCGCCGCCGCC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000094 ( 0 hom., 0 hem., cov: 18)

Exomes 𝑓: 0.0000022 ( 0 hom. 0 hem. )

Consequence

KDM6A
NM_001291415.2 5_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.304

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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.-176_-165dupGCCGCCGCCGCC	5_prime_UTR	Exon 1 of 30	NP_001278344.1	A0A087X0R0
KDM6A	NM_001419809.1		c.-176_-165dupGCCGCCGCCGCC	5_prime_UTR	Exon 1 of 31	NP_001406738.1
KDM6A	NM_001419810.1		c.-176_-165dupGCCGCCGCCGCC	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.-176_-165dupGCCGCCGCCGCC	5_prime_UTR	Exon 1 of 30	ENSP00000483595.2	A0A087X0R0
KDM6A	ENST00000382899.9	TSL:1	c.-176_-165dupGCCGCCGCCGCC	5_prime_UTR	Exon 1 of 29	ENSP00000372355.6	F8W8R6
KDM6A	ENST00000377967.9	TSL:1	c.-176_-165dupGCCGCCGCCGCC	5_prime_UTR	Exon 1 of 29	ENSP00000367203.4	O15550

Frequencies

GnomAD3 genomes

AF:

0.00000942

AC:

AN:

106154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000347

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

GnomAD4 exome

AF:

0.00000217

AC:

AN:

460279

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

114251

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

8791

American (AMR)

AF:

0.00

AC:

AN:

11929

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8836

East Asian (EAS)

AF:

0.00

AC:

AN:

18251

South Asian (SAS)

AF:

0.00

AC:

AN:

29090

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26775

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1400

European-Non Finnish (NFE)

AF:

0.00000300

AC:

AN:

333454

Other (OTH)

AF:

0.00

AC:

AN:

21753

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.00000942

AC:

AN:

106154

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

29872

show subpopulations

African (AFR)

AF:

0.0000347

AC:

AN:

28859

American (AMR)

AF:

0.00

AC:

AN:

10164

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2592

East Asian (EAS)

AF:

0.00

AC:

AN:

3146

South Asian (SAS)

AF:

0.00

AC:

AN:

2339

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5318

Middle Eastern (MID)

AF:

0.00

AC:

AN:

223

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

51434

Other (OTH)

AF:

0.00

AC:

AN:

1427

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.30

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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X-44873369-TGCCGCCGCCGCC-TGCCGCCGCCGCCGCCGCCGCCGCC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over