rs61751429

Variant names:

• chrX-45062751-G-A
• rs61751429
• NM_001291415.2:c.1683+3G>A

Variant summary

Our verdict is Benign. The variant received -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 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. 3/3 splice prediction tools predict no significant impact on normal splicing. 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_region, intron
• Scores: Splicing: ADA: 0.0001326
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.965
• Publications: 1 publications found

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: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• Kabuki syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 261406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 307 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM6A	NM_001291415.2	MANE Select	c.1683+3G>A		splice_region intron	N/A	NP_001278344.1
	KDM6A	NM_001419809.1		c.1683+3G>A		splice_region intron	N/A	NP_001406738.1
	KDM6A	NM_001419810.1		c.1582-671G>A		intron	N/A	NP_001406739.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM6A	ENST00000611820.5	TSL:1 MANE Select	c.1683+3G>A		splice_region intron	N/A	ENSP00000483595.2
	KDM6A	ENST00000382899.9	TSL:1	c.1548+3G>A		splice_region intron	N/A	ENSP00000372355.6
	KDM6A	ENST00000377967.9	TSL:1	c.1527+3G>A		splice_region intron	N/A	ENSP00000367203.4

Frequencies

GnomAD3 genomes AF: 0.00274 AC: 307 AN: 112161 Hom.: 1 Cov.: 22

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

GnomAD2 exomes AF: 0.00254 AC: 460 AN: 181089 AF XY: 0.00270

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 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

African (AFR) AF: 0.000326 AC: 8 AN: 24546

American (AMR) AF: 0.000514 AC: 18 AN: 35036

Ashkenazi Jewish (ASJ) AF: 0.00357 AC: 67 AN: 18761

East Asian (EAS) AF: 0.00 AC: 0 AN: 29762

South Asian (SAS) AF: 0.000116 AC: 6 AN: 51708

European-Finnish (FIN) AF: 0.00611 AC: 247 AN: 40429

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3821

European-Non Finnish (NFE) AF: 0.00469 AC: 3538 AN: 754320

Other (OTH) AF: 0.00249 AC: 107 AN: 42932

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

African (AFR) AF: 0.000388 AC: 12 AN: 30957

American (AMR) AF: 0.000471 AC: 5 AN: 10606

Ashkenazi Jewish (ASJ) AF: 0.00189 AC: 5 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3572

South Asian (SAS) AF: 0.00 AC: 0 AN: 2747

European-Finnish (FIN) AF: 0.00516 AC: 31 AN: 6013

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.00473 AC: 252 AN: 53228

Other (OTH) AF: 0.00130 AC: 2 AN: 1543

Alfa AF: 0.00270 Hom.: 17

Bravo AF: 0.00220

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Kabuki syndrome 2 (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	15
DANN	Benign	0.85
PhyloP100		0.96
Mutation Taster		=14/86	polymorphism (auto)

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

Other links and lift over

dbSNP: rs61751429; hg19: chrX-44921996;