NM_001291415.2:c.88G>A

Variant names:

• chrX-44873639-G-A
• rs6529
• NM_001291415.2:c.88G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001291415.2(KDM6A):​c.88G>A​(p.Ala30Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000333 in 1,193,516 control chromosomes in the GnomAD database, including 1 homozygotes. There are 102 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., 52 hem., cov: 23)
  • Exomes 𝑓: 0.00018 (1 hom. 50 hem.)
• Consequence: KDM6A NM_001291415.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 5.44
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0070658326).
• BP6: Variant X-44873639-G-A is Benign according to our data. Variant chrX-44873639-G-A is described in ClinVar as Benign. ClinVar VariationId is 134594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00179 (202/112883) while in subpopulation AFR AF = 0.00622 (194/31187). AF 95% confidence interval is 0.0055. There are 0 homozygotes in GnomAd4. There are 52 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 202 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.88G>A	p.Ala30Thr	missense	Exon 1 of 30	NP_001278344.1	A0A087X0R0
	KDM6A	NM_001419809.1		c.88G>A	p.Ala30Thr	missense	Exon 1 of 31	NP_001406738.1
	KDM6A	NM_001419810.1		c.88G>A	p.Ala30Thr	missense	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.88G>A	p.Ala30Thr	missense	Exon 1 of 30	ENSP00000483595.2	A0A087X0R0
	KDM6A	ENST00000382899.9	TSL:1	c.88G>A	p.Ala30Thr	missense	Exon 1 of 29	ENSP00000372355.6	F8W8R6
	KDM6A	ENST00000377967.9	TSL:1	c.88G>A	p.Ala30Thr	missense	Exon 1 of 29	ENSP00000367203.4	O15550

Frequencies

GnomAD3 genomes AF: 0.00180 AC: 203 AN: 112836 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000185

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: 0.0000564

Gnomad OTH AF: 0.00197

GnomAD2 exomes AF: 0.000376 AC: 53 AN: 141040 AF XY: 0.000202

Gnomad AFR exome AF: 0.00555

Gnomad AMR exome AF: 0.000169

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000174

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000180 AC: 195 AN: 1080633 Hom.: 1 Cov.: 32 AF XY: 0.000142 AC XY: 50 AN XY: 351807

African (AFR) AF: 0.00682 AC: 178 AN: 26104

American (AMR) AF: 0.000185 AC: 6 AN: 32483

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19085

East Asian (EAS) AF: 0.00 AC: 0 AN: 29412

South Asian (SAS) AF: 0.00 AC: 0 AN: 52371

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38078

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3831

European-Non Finnish (NFE) AF: 0.00000240 AC: 2 AN: 833902

Other (OTH) AF: 0.000198 AC: 9 AN: 45367

GnomAD4 genome AF: 0.00179 AC: 202 AN: 112883 Hom.: 0 Cov.: 23 AF XY: 0.00148 AC XY: 52 AN XY: 35057

African (AFR) AF: 0.00622 AC: 194 AN: 31187

American (AMR) AF: 0.000185 AC: 2 AN: 10817

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3527

South Asian (SAS) AF: 0.00 AC: 0 AN: 2809

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6234

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.0000564 AC: 3 AN: 53215

Other (OTH) AF: 0.00195 AC: 3 AN: 1539

Alfa AF: 0.00141 Hom.: 10

Bravo AF: 0.00248

ESP6500AA AF: 0.00353 AC: 13

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000421 AC: 49

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Intellectual disability (1)
-	-	1	Kabuki syndrome 2 (1)
-	-	1	KDM6A-related disorder (1)
-	-	1	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.056	T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Benign	0.0071	T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.4
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.023	D
Polyphen		0.77	P
Vest4		0.54
MVP		0.72
MPC		1.2
ClinPred		0.060	T
GERP RS		3.8
PromoterAI		-0.018	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.55
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs6529; hg19: chrX-44732885; COSMIC: COSV65039502; COSMIC: COSV65039502;