rs1555934050

Variant names:

• chrX-41216601-T-A
• rs1555934050
• NM_001039591.3:c.6034T>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001039591.3(USP9X):​c.6034T>A​(p.Phe2012Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: USP9X NM_001039591.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67
• Publications: 0 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867

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.6034T>A	p.Phe2012Ile	missense	Exon 35 of 45	NP_001034680.2	Q93008-1
	USP9X	NM_001410748.1		c.6049T>A	p.Phe2017Ile	missense	Exon 36 of 46	NP_001397677.1	A0A994J4R6
	USP9X	NM_001039590.3		c.6034T>A	p.Phe2012Ile	missense	Exon 35 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.6034T>A	p.Phe2012Ile	missense	Exon 35 of 45	ENSP00000367558.2	Q93008-1
	USP9X	ENST00000703987.1		c.6049T>A	p.Phe2017Ile	missense	Exon 35 of 45	ENSP00000515604.1	A0A994J4R6
	USP9X	ENST00000324545.9	TSL:5	c.6034T>A	p.Phe2012Ile	missense	Exon 35 of 45	ENSP00000316357.6	Q93008-3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.7
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.018	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.54		Loss of catalytic residue at F2012 (P = 0.0469)
MVP		0.91
MPC		2.4
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.87
gMVP		0.93
Mutation Taster		=13/87	disease causing

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: rs1555934050; hg19: chrX-41075854;