Genetic Variant KDM6A:c.-167_-165delGCC (chrX-44873369-TGCC-T) – 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.-167_-165delGCC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000549 in 457,496 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., 0 hem., cov: 18)

Exomes 𝑓: 0.00055 ( 0 hom. 2 hem. )

Failed GnomAD Quality Control

Consequence

KDM6A
NM_001291415.2 5_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0770

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.-167_-165delGCC	5_prime_UTR	Exon 1 of 30	NP_001278344.1	A0A087X0R0
KDM6A	NM_001419809.1		c.-167_-165delGCC	5_prime_UTR	Exon 1 of 31	NP_001406738.1
KDM6A	NM_001419810.1		c.-167_-165delGCC	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.-167_-165delGCC	5_prime_UTR	Exon 1 of 30	ENSP00000483595.2	A0A087X0R0
KDM6A	ENST00000382899.9	TSL:1	c.-167_-165delGCC	5_prime_UTR	Exon 1 of 29	ENSP00000372355.6	F8W8R6
KDM6A	ENST00000377967.9	TSL:1	c.-167_-165delGCC	5_prime_UTR	Exon 1 of 29	ENSP00000367203.4	O15550

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

106147

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

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:

0.000549

AC:

251

AN:

457496

Hom.:

AF XY:

0.0000177

AC XY:

AN XY:

113098

show subpopulations

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

African (AFR)

AF:

0.000571

AC:

AN:

8761

American (AMR)

AF:

0.00110

AC:

AN:

11807

Ashkenazi Jewish (ASJ)

AF:

0.000342

AC:

AN:

8774

East Asian (EAS)

AF:

0.000386

AC:

AN:

18137

South Asian (SAS)

AF:

0.000173

AC:

AN:

28905

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

26578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1393

European-Non Finnish (NFE)

AF:

0.000621

AC:

206

AN:

331504

Other (OTH)

AF:

0.000324

AC:

AN:

21637

⚠️ 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: 0.233

Heterozygous variant carriers

139

186

232

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

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

106179

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

29911

African (AFR)

AF:

0.00

AC:

AN:

28908

American (AMR)

AF:

0.00

AC:

AN:

10177

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2592

East Asian (EAS)

AF:

0.00

AC:

AN:

3131

South Asian (SAS)

AF:

0.00

AC:

AN:

2332

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5316

Middle Eastern (MID)

AF:

0.00

AC:

AN:

201

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

51426

Other (OTH)

AF:

0.00

AC:

AN:

1444

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.077

Splicing

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

Publications

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X-44873369-TGCCGCCGCCGCC-TGCCGCCGCC

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