rs34922269

Variant names:

• chrX-45063635-A-G
• rs34922269
• NM_001291415.2:c.1897A>G

Your query was ambiguous. Multiple possible variants found:

• chrX-45063635-A-G
• chrX-45063635-A-T

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.1897A>G​(p.Thr633Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00114 in 1,208,652 control chromosomes in the GnomAD database, including 9 homozygotes. There are 363 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (5 hom., 166 hem., cov: 22)
  • Exomes 𝑓: 0.00066 (4 hom. 197 hem.)
• Consequence: KDM6A NM_001291415.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 6.71
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007016927).
• BP6: Variant X-45063635-A-G is Benign according to our data. Variant chrX-45063635-A-G is described in ClinVar as Benign. ClinVar VariationId is 261405.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 = 0.00585 (653/111626) while in subpopulation AFR AF = 0.02 (615/30687). AF 95% confidence interval is 0.0187. There are 5 homozygotes in GnomAd4. There are 166 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 653 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.1897A>G	p.Thr633Ala	missense	Exon 17 of 30	NP_001278344.1	A0A087X0R0
	KDM6A	NM_001419809.1		c.1897A>G	p.Thr633Ala	missense	Exon 17 of 31	NP_001406738.1
	KDM6A	NM_001419810.1		c.1795A>G	p.Thr599Ala	missense	Exon 16 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.1897A>G	p.Thr633Ala	missense	Exon 17 of 30	ENSP00000483595.2	A0A087X0R0
	KDM6A	ENST00000382899.9	TSL:1	c.1762A>G	p.Thr588Ala	missense	Exon 16 of 29	ENSP00000372355.6	F8W8R6
	KDM6A	ENST00000377967.9	TSL:1	c.1741A>G	p.Thr581Ala	missense	Exon 16 of 29	ENSP00000367203.4	O15550

Frequencies

GnomAD3 genomes AF: 0.00583 AC: 650 AN: 111574 Hom.: 5 Cov.: 22

Gnomad AFR AF: 0.0200

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00247

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000371

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000151

Gnomad OTH AF: 0.00266

GnomAD2 exomes AF: 0.00175 AC: 317 AN: 181660 AF XY: 0.00110

Gnomad AFR exome AF: 0.0213

Gnomad AMR exome AF: 0.00106

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000989

Gnomad OTH exome AF: 0.000223

GnomAD4 exome AF: 0.000657 AC: 721 AN: 1097026 Hom.: 4 Cov.: 30 AF XY: 0.000544 AC XY: 197 AN XY: 362408

African (AFR) AF: 0.0213 AC: 562 AN: 26387

American (AMR) AF: 0.00134 AC: 47 AN: 35164

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19375

East Asian (EAS) AF: 0.00 AC: 0 AN: 30190

South Asian (SAS) AF: 0.0000740 AC: 4 AN: 54037

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40493

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4135

European-Non Finnish (NFE) AF: 0.0000499 AC: 42 AN: 841192

Other (OTH) AF: 0.00141 AC: 65 AN: 46053

GnomAD4 genome AF: 0.00585 AC: 653 AN: 111626 Hom.: 5 Cov.: 22 AF XY: 0.00491 AC XY: 166 AN XY: 33820

African (AFR) AF: 0.0200 AC: 615 AN: 30687

American (AMR) AF: 0.00247 AC: 26 AN: 10528

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3540

South Asian (SAS) AF: 0.00 AC: 0 AN: 2688

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6018

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

European-Non Finnish (NFE) AF: 0.000151 AC: 8 AN: 53098

Other (OTH) AF: 0.00263 AC: 4 AN: 1523

Alfa AF: 0.00305 Hom.: 143

Bravo AF: 0.00677

ESP6500AA AF: 0.0167 AC: 64

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00193 AC: 234

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Kabuki syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.025	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PhyloP100		6.7
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.21
Sift	Uncertain	0.013	D
Sift4G	Benign	0.74	T
Polyphen		0.82	P
Vest4		0.46
MVP		0.48
MPC		0.11
ClinPred		0.052	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.43
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34922269; hg19: chrX-44922880;