X-41123644-C-T

Variant names:

• chrX-41123644-C-T
• rs1466172330
• NM_001039591.3:c.16C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001039591.3(USP9X):​c.16C>T​(p.Arg6Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R6H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: USP9X NM_001039591.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.57
• Publications: 2 publications found

Genes affected

USP9X (HGNC:12632): (ubiquitin specific peptidase 9 X-linked) This gene is a member of the peptidase C19 family and encodes a protein that is similar to ubiquitin-specific proteases. Though this gene is located on the X chromosome, it escapes X-inactivation. Mutations in this gene have been associated with Turner syndrome. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

USP9X Gene-Disease associations (from GenCC):

• intellectual disability, X-linked 99, syndromic, female-restricted

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• X-linked syndromic intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• intellectual disability, X-linked 99

  Inheritance: XL Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked female restricted facial dysmorphism-short stature-choanal atresia-intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039591.3. 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
	USP9X	NM_001039591.3	MANE Select	c.16C>T	p.Arg6Cys	missense	Exon 2 of 45	NP_001034680.2	Q93008-1
	USP9X	NM_001410748.1		c.16C>T	p.Arg6Cys	missense	Exon 3 of 46	NP_001397677.1	A0A994J4R6
	USP9X	NM_001039590.3		c.16C>T	p.Arg6Cys	missense	Exon 2 of 45	NP_001034679.2	Q93008-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP9X	ENST00000378308.7	TSL:5 MANE Select	c.16C>T	p.Arg6Cys	missense	Exon 2 of 45	ENSP00000367558.2	Q93008-1
	USP9X	ENST00000703987.1		c.16C>T	p.Arg6Cys	missense	Exon 2 of 45	ENSP00000515604.1	A0A994J4R6
	USP9X	ENST00000324545.9	TSL:5	c.16C>T	p.Arg6Cys	missense	Exon 2 of 45	ENSP00000316357.6	Q93008-3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	Intellectual disability, X-linked 99 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.54	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	2.0	M
PhyloP100		7.6
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.63
MutPred		0.38		Loss of MoRF binding (P = 4e-04)
MVP		0.56
MPC		1.6
ClinPred		0.98	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.73
gMVP		0.41
Mutation Taster		=50/50

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: rs1466172330; hg19: chrX-40982897;