rs201673109

Variant names:

• chrX-45076726-G-C
• rs201673109
• NM_001291415.2:c.2888G>C

Your query was ambiguous. Multiple possible variants found:

• chrX-45076726-G-C
• chrX-45076726-G-A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_001291415.2(KDM6A):​c.2888G>C​(p.Ser963Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000501 in 1,157,800 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 27 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000041 (0 hom., 1 hem., cov: 20)
  • Exomes 𝑓: 0.000051 (0 hom. 26 hem.)
• Consequence: KDM6A NM_001291415.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:2 O:1
• Conservation: PhyloP100: 6.39
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10689333).
• BP6: Variant X-45076726-G-C is Benign according to our data. Variant chrX-45076726-G-C is described in ClinVar as Benign. ClinVar VariationId is 134598.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000408 (4/97981) while in subpopulation SAS AF = 0.000961 (2/2082). AF 95% confidence interval is 0.00017. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 54 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.2888G>C	p.Ser963Thr	missense	Exon 19 of 30	NP_001278344.1	A0A087X0R0
	KDM6A	NM_001419809.1		c.2888G>C	p.Ser963Thr	missense	Exon 19 of 31	NP_001406738.1
	KDM6A	NM_001419810.1		c.2786G>C	p.Ser929Thr	missense	Exon 18 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.2888G>C	p.Ser963Thr	missense	Exon 19 of 30	ENSP00000483595.2	A0A087X0R0
	KDM6A	ENST00000382899.9	TSL:1	c.2753G>C	p.Ser918Thr	missense	Exon 18 of 29	ENSP00000372355.6	F8W8R6
	KDM6A	ENST00000377967.9	TSL:1	c.2732G>C	p.Ser911Thr	missense	Exon 18 of 29	ENSP00000367203.4	O15550

Frequencies

GnomAD3 genomes AF: 0.0000408 AC: 4 AN: 97949 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000955

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000403

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000659 AC: 12 AN: 181991 AF XY: 0.000105

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000510 AC: 54 AN: 1059819 Hom.: 0 Cov.: 26 AF XY: 0.0000780 AC XY: 26 AN XY: 333487

African (AFR) AF: 0.00 AC: 0 AN: 25554

American (AMR) AF: 0.00 AC: 0 AN: 34811

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18910

East Asian (EAS) AF: 0.00 AC: 0 AN: 29621

South Asian (SAS) AF: 0.000397 AC: 21 AN: 52903

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40145

Middle Eastern (MID) AF: 0.00150 AC: 6 AN: 3991

European-Non Finnish (NFE) AF: 0.0000309 AC: 25 AN: 809293

Other (OTH) AF: 0.0000449 AC: 2 AN: 44591

GnomAD4 genome AF: 0.0000408 AC: 4 AN: 97981 Hom.: 0 Cov.: 20 AF XY: 0.0000404 AC XY: 1 AN XY: 24767

African (AFR) AF: 0.00 AC: 0 AN: 26056

American (AMR) AF: 0.00 AC: 0 AN: 8262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2506

East Asian (EAS) AF: 0.00 AC: 0 AN: 3196

South Asian (SAS) AF: 0.000961 AC: 2 AN: 2082

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4143

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 161

European-Non Finnish (NFE) AF: 0.0000403 AC: 2 AN: 49663

Other (OTH) AF: 0.00 AC: 0 AN: 1265

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000659 AC: 8

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Benign	0.11	T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	1.9	L
PhyloP100		6.4
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.41
Sift	Benign	0.14	T
Sift4G	Benign	0.44	T
Polyphen		0.86	P
Vest4		0.15
MVP		0.71
MPC		0.10
ClinPred		0.15	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
gMVP		0.29
Mutation Taster		=98/2	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: rs201673109; hg19: chrX-44935971;