rs1373790479

Variant names:

• chrX-44961308-A-G
• rs1373790479
• NM_001291415.2:c.250A>G

Your query was ambiguous. Multiple possible variants found:

• chrX-44961308-A-G
• chrX-44961308-A-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001291415.2(KDM6A):​c.250A>G​(p.Ile84Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000734 in 1,090,607 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I84N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.0000073 (0 hom. 2 hem.)
  • Failed GnomAD Quality Control
• Consequence: KDM6A NM_001291415.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:2
• Conservation: PhyloP100: 8.70
• Publications: 1 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3136741).
• BS2: High AC in GnomAdExome4 at 8 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.250A>G	p.Ile84Val	missense	Exon 3 of 30	NP_001278344.1	A0A087X0R0
	KDM6A	NM_001419809.1		c.250A>G	p.Ile84Val	missense	Exon 3 of 31	NP_001406738.1
	KDM6A	NM_001419810.1		c.250A>G	p.Ile84Val	missense	Exon 3 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.250A>G	p.Ile84Val	missense	Exon 3 of 30	ENSP00000483595.2	A0A087X0R0
	KDM6A	ENST00000382899.9	TSL:1	c.250A>G	p.Ile84Val	missense	Exon 3 of 29	ENSP00000372355.6	F8W8R6
	KDM6A	ENST00000377967.9	TSL:1	c.250A>G	p.Ile84Val	missense	Exon 3 of 29	ENSP00000367203.4	O15550

Frequencies

GnomAD3 genomes AF: 0.00000895 AC: 1 AN: 111685 Hom.: 0 Cov.: 23

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000734 AC: 8 AN: 1090607 Hom.: 0 Cov.: 27 AF XY: 0.00000560 AC XY: 2 AN XY: 357241

African (AFR) AF: 0.00 AC: 0 AN: 26245

American (AMR) AF: 0.00 AC: 0 AN: 35147

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19307

East Asian (EAS) AF: 0.00 AC: 0 AN: 30081

South Asian (SAS) AF: 0.00 AC: 0 AN: 53877

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40430

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3335

European-Non Finnish (NFE) AF: 0.00000956 AC: 8 AN: 836431

Other (OTH) AF: 0.00 AC: 0 AN: 45754

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000895 AC: 1 AN: 111685 Hom.: 0 Cov.: 23 AF XY: 0.0000295 AC XY: 1 AN XY: 33899

African (AFR) AF: 0.00 AC: 0 AN: 30772

American (AMR) AF: 0.00 AC: 0 AN: 10462

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2647

East Asian (EAS) AF: 0.00 AC: 0 AN: 3592

South Asian (SAS) AF: 0.00 AC: 0 AN: 2682

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6067

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 53018

Other (OTH) AF: 0.00 AC: 0 AN: 1520

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	2	-	Kabuki syndrome 2 (2)
1	-	-	CHARGE syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.020	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	0.019	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		8.7
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.22
Sift	Benign	0.062	T
Sift4G	Benign	0.28	T
Polyphen		0.39	B
Vest4		0.32
MutPred		0.36		Gain of ubiquitination at K86 (P = 0.1378)
MVP		0.62
MPC		0.81
ClinPred		0.86	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.22
Mutation Taster		=91/9	disease causing (ClinVar)

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: rs1373790479; hg19: chrX-44820553;