rs141353229

Variant names:

• chrX-45063645-C-T
• rs141353229
• NM_001291415.2:c.1907C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-45063645-C-T
• chrX-45063645-C-A
• chrX-45063645-C-G

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.1907C>T​(p.Thr636Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,208,526 control chromosomes in the GnomAD database, including 1 homozygotes. There are 425 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T636T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00076 (0 hom., 24 hem., cov: 22)
  • Exomes 𝑓: 0.0011 (1 hom. 401 hem.)
• Consequence: KDM6A NM_001291415.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 2.50
• Publications: 8 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=0.01359275).
• BP6: Variant X-45063645-C-T is Benign according to our data. Variant chrX-45063645-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 284402.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 = 0.000762 (85/111588) while in subpopulation NFE AF = 0.00143 (76/53115). AF 95% confidence interval is 0.00117. There are 0 homozygotes in GnomAd4. There are 24 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 85 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.1907C>T	p.Thr636Met	missense	Exon 17 of 30	NP_001278344.1	A0A087X0R0
	KDM6A	NM_001419809.1		c.1907C>T	p.Thr636Met	missense	Exon 17 of 31	NP_001406738.1
	KDM6A	NM_001419810.1		c.1805C>T	p.Thr602Met	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.1907C>T	p.Thr636Met	missense	Exon 17 of 30	ENSP00000483595.2	A0A087X0R0
	KDM6A	ENST00000382899.9	TSL:1	c.1772C>T	p.Thr591Met	missense	Exon 16 of 29	ENSP00000372355.6	F8W8R6
	KDM6A	ENST00000377967.9	TSL:1	c.1751C>T	p.Thr584Met	missense	Exon 16 of 29	ENSP00000367203.4	O15550

Frequencies

GnomAD3 genomes AF: 0.000762 AC: 85 AN: 111538 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000954

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000667

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00143

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000789 AC: 143 AN: 181140 AF XY: 0.000943

Gnomad AFR exome AF: 0.000230

Gnomad AMR exome AF: 0.000220

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.00127

Gnomad NFE exome AF: 0.00132

Gnomad OTH exome AF: 0.000893

GnomAD4 exome AF: 0.00112 AC: 1233 AN: 1096938 Hom.: 1 Cov.: 31 AF XY: 0.00111 AC XY: 401 AN XY: 362320

African (AFR) AF: 0.000114 AC: 3 AN: 26389

American (AMR) AF: 0.000228 AC: 8 AN: 35135

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19373

East Asian (EAS) AF: 0.000132 AC: 4 AN: 30190

South Asian (SAS) AF: 0.0000370 AC: 2 AN: 54008

European-Finnish (FIN) AF: 0.00114 AC: 46 AN: 40479

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4136

European-Non Finnish (NFE) AF: 0.00134 AC: 1125 AN: 841179

Other (OTH) AF: 0.000956 AC: 44 AN: 46049

GnomAD4 genome AF: 0.000762 AC: 85 AN: 111588 Hom.: 0 Cov.: 22 AF XY: 0.000710 AC XY: 24 AN XY: 33800

African (AFR) AF: 0.000130 AC: 4 AN: 30675

American (AMR) AF: 0.0000952 AC: 1 AN: 10500

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3552

South Asian (SAS) AF: 0.00 AC: 0 AN: 2678

European-Finnish (FIN) AF: 0.000667 AC: 4 AN: 5999

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

European-Non Finnish (NFE) AF: 0.00143 AC: 76 AN: 53115

Other (OTH) AF: 0.00 AC: 0 AN: 1528

Alfa AF: 0.00124 Hom.: 67

Bravo AF: 0.000665

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00173 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00193 AC: 13

ExAC AF: 0.000972 AC: 118

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	Kabuki syndrome 2 (3)
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	KDM6A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0084	T
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		2.5
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.047
Sift	Uncertain	0.024	D
Sift4G	Benign	0.26	T
Polyphen		0.76	P
Vest4		0.054
MVP		0.20
MPC		0.11
ClinPred		0.0088	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.067
gMVP		0.34
Mutation Taster		=95/5	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: rs141353229; hg19: chrX-44922890; COSMIC: COSV104429198;