rs61751429

chrX-45062751-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001291415.2(KDM6A):c.1683+3G>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00386 in 1,113,530 control chromosomes in the GnomAD database, including 7 homozygotes. There are 1,207 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 0.0027 (1 hom., 78 hem., cov: 22)
  • Exomes 𝑓: 0.0040 (6 hom. 1129 hem.)
• Consequence: KDM6A NM_001291415.2 splice_donor_region, intron
• Scores: Splicing: ADA: 0.0001326
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.965

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant X-45062751-G-A is Benign according to our data. Variant chrX-45062751-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 261406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-45062751-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00274 (307/112215) while in subpopulation NFE AF= 0.00473 (252/53228). AF 95% confidence interval is 0.00425. There are 1 homozygotes in gnomad4. There are 78 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 78 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KDM6A	NM_001291415.2	c.1683+3G>A		splice_donor_region_variant, intron_variant		ENST00000611820.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KDM6A	ENST00000611820.5	c.1683+3G>A		splice_donor_region_variant, intron_variant		1	NM_001291415.2	P4

Frequencies

GnomAD3 genomes AF: 0.00274 AC: 307 AN: 112161 Hom.: 1 Cov.: 22 AF XY: 0.00227 AC XY: 78 AN XY: 34319

Gnomad AFR AF: 0.000389

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000472

Gnomad ASJ AF: 0.00189

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00516

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00473

Gnomad OTH AF: 0.00131

GnomAD3 exomes AF: 0.00254 AC: 460 AN: 181089 Hom.: 0 AF XY: 0.00270 AC XY: 178 AN XY: 65817

Gnomad AFR exome AF: 0.000620

Gnomad AMR exome AF: 0.000624

Gnomad ASJ exome AF: 0.00352

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000161

Gnomad FIN exome AF: 0.00559

Gnomad NFE exome AF: 0.00383

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00399 AC: 3991 AN: 1001315 Hom.: 6 Cov.: 20 AF XY: 0.00392 AC XY: 1129 AN XY: 288221

Gnomad4 AFR exome AF: 0.000326

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.00357

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00611

Gnomad4 NFE exome AF: 0.00469

Gnomad4 OTH exome AF: 0.00249

GnomAD4 genome AF: 0.00274 AC: 307 AN: 112215 Hom.: 1 Cov.: 22 AF XY: 0.00227 AC XY: 78 AN XY: 34383

Gnomad4 AFR AF: 0.000388

Gnomad4 AMR AF: 0.000471

Gnomad4 ASJ AF: 0.00189

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00516

Gnomad4 NFE AF: 0.00473

Gnomad4 OTH AF: 0.00130

Alfa AF: 0.00270 Hom.: 17

Bravo AF: 0.00220

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 24, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 18, 2018	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Kabuki syndrome 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 15, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
Cadd	Benign	15
Dann	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00013
dbscSNV1_RF	Benign	0.072
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

LitVar

Other links and lift over

dbSNP: rs61751429; hg19: chrX-44921996;