X-44873369-TGCCGCCGCCGCC-TGCCGCCGCCGCCGCCGCC

Variant names:

• chrX-44873369-T-TGCCGCC
• rs762577042
• NM_001291415.2:c.-170_-165dupGCCGCC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001291415.2(KDM6A):​c.-170_-165dupGCCGCC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0040 (3 hom., 112 hem., cov: 18)
  • Exomes 𝑓: 0.0047 (7 hom. 586 hem.)
• Consequence: KDM6A NM_001291415.2 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.304
• Publications: 0 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• Kabuki syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant X-44873369-T-TGCCGCC is Benign according to our data. Variant chrX-44873369-T-TGCCGCC is described in ClinVar as Likely_benign. ClinVar VariationId is 1198356.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00401 (426/106173) while in subpopulation NFE AF = 0.00544 (280/51424). AF 95% confidence interval is 0.00492. There are 3 homozygotes in GnomAd4. There are 112 alleles in the male GnomAd4 subpopulation. Median coverage is 18. This position passed quality control check.
• BS2: High AC in GnomAd4 at 426 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM6A	NM_001291415.2	MANE Select	c.-170_-165dupGCCGCC		5_prime_UTR	Exon 1 of 30	NP_001278344.1	A0A087X0R0
	KDM6A	NM_001419809.1		c.-170_-165dupGCCGCC		5_prime_UTR	Exon 1 of 31	NP_001406738.1
	KDM6A	NM_001419810.1		c.-170_-165dupGCCGCC		5_prime_UTR	Exon 1 of 30	NP_001406739.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM6A	ENST00000611820.5	TSL:1 MANE Select	c.-170_-165dupGCCGCC		5_prime_UTR	Exon 1 of 30	ENSP00000483595.2	A0A087X0R0
	KDM6A	ENST00000382899.9	TSL:1	c.-170_-165dupGCCGCC		5_prime_UTR	Exon 1 of 29	ENSP00000372355.6	F8W8R6
	KDM6A	ENST00000377967.9	TSL:1	c.-170_-165dupGCCGCC		5_prime_UTR	Exon 1 of 29	ENSP00000367203.4	O15550

Frequencies

GnomAD3 genomes AF: 0.00401 AC: 426 AN: 106141 Hom.: 3 Cov.: 18

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00307

Gnomad AMR AF: 0.000885

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000855

Gnomad FIN AF: 0.0179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00544

Gnomad OTH AF: 0.00210

GnomAD4 exome AF: 0.00475 AC: 2185 AN: 460185 Hom.: 7 Cov.: 8 AF XY: 0.00513 AC XY: 586 AN XY: 114205

African (AFR) AF: 0.000796 AC: 7 AN: 8790

American (AMR) AF: 0.000922 AC: 11 AN: 11928

Ashkenazi Jewish (ASJ) AF: 0.000113 AC: 1 AN: 8836

East Asian (EAS) AF: 0.000329 AC: 6 AN: 18250

South Asian (SAS) AF: 0.000619 AC: 18 AN: 29087

European-Finnish (FIN) AF: 0.0245 AC: 656 AN: 26751

Middle Eastern (MID) AF: 0.00143 AC: 2 AN: 1400

European-Non Finnish (NFE) AF: 0.00417 AC: 1390 AN: 333400

Other (OTH) AF: 0.00432 AC: 94 AN: 21743

GnomAD4 genome AF: 0.00401 AC: 426 AN: 106173 Hom.: 3 Cov.: 18 AF XY: 0.00375 AC XY: 112 AN XY: 29903

African (AFR) AF: 0.00121 AC: 35 AN: 28907

American (AMR) AF: 0.000884 AC: 9 AN: 10177

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2592

East Asian (EAS) AF: 0.00 AC: 0 AN: 3131

South Asian (SAS) AF: 0.000858 AC: 2 AN: 2332

European-Finnish (FIN) AF: 0.0179 AC: 95 AN: 5313

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 201

European-Non Finnish (NFE) AF: 0.00544 AC: 280 AN: 51424

Other (OTH) AF: 0.00208 AC: 3 AN: 1444

Alfa AF: 0.00342 Hom.: 99

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

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

Other links and lift over

dbSNP: rs762577042; hg19: chrX-44732615;