Genetic Variant KDM6A:c.2859-7_2859-5delTTT (chrX-45076679-CTTT-C) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_001291415.2(KDM6A):c.2859-7_2859-5delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 805,245 control chromosomes in the GnomAD database, including 2 homozygotes. There are 23 hemizygotes in GnomAD. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., 2 hem., cov: 0)

Exomes 𝑓: 0.0020 ( 2 hom. 21 hem. )

Consequence

KDM6A
NM_001291415.2 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.198

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant X-45076679-CTTT-C is Benign according to our data. Variant chrX-45076679-CTTT-C is described in ClinVar as [Benign]. Clinvar id is 194885.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000158 (14/88378) while in subpopulation EAS AF= 0.00208 (6/2888). AF 95% confidence interval is 0.000904. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDM6A	NM_001291415.2 link	c.2859-7_2859-5delTTT		splice_region_variant, intron_variant	Intron 18 of 29	ENST00000611820.5	NP_001278344.1	A0A087X0R0B7ZKN5Q86TD1B7ZKN6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KDM6A	ENST00000611820.5 link	c.2859-7_2859-5delTTT		splice_region_variant, intron_variant	Intron 18 of 29	1	NM_001291415.2	ENSP00000483595.2		A0A087X0R0

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

88373

Hom.:

Cov.:

AF XY:

0.000119

AC XY:

AN XY:

16775

show subpopulations

Gnomad AFR

AF:

0.000122

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00207

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000793

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000667

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00386

AC:

306

AN:

79362

Hom.:

AF XY:

0.000716

AC XY:

AN XY:

6988

show subpopulations

Gnomad AFR exome

AF:

0.000781

Gnomad AMR exome

AF:

0.00196

Gnomad ASJ exome

AF:

0.00159

Gnomad EAS exome

AF:

0.0140

Gnomad SAS exome

AF:

0.00618

Gnomad FIN exome

AF:

0.00306

Gnomad NFE exome

AF:

0.00305

Gnomad OTH exome

AF:

0.00358

GnomAD4 exome

AF:

0.00198

AC:

1417

AN:

716867

Hom.:

AF XY:

0.000105

AC XY:

AN XY:

199911

show subpopulations

Gnomad4 AFR exome

AF:

0.00123

Gnomad4 AMR exome

AF:

0.00115

Gnomad4 ASJ exome

AF:

0.00110

Gnomad4 EAS exome

AF:

0.00866

Gnomad4 SAS exome

AF:

0.00262

Gnomad4 FIN exome

AF:

0.00211

Gnomad4 NFE exome

AF:

0.00169

Gnomad4 OTH exome

AF:

0.00256

GnomAD4 genome

AF:

0.000158

AC:

AN:

88378

Hom.:

Cov.:

AF XY:

0.000119

AC XY:

AN XY:

16796

show subpopulations

Gnomad4 AFR

AF:

0.000122

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00208

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000793

Gnomad4 NFE

AF:

0.0000667

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0111

Hom.:

1920

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Dec 10, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

May 10, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Kabuki syndrome 2

Benign:1

Jul 19, 2021

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

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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.

X-45076679-CTTTT-CT

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