X-41123705-C-G

Variant names:

• chrX-41123705-C-G
• rs767741303
• NM_001039591.3:c.77C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001039591.3(USP9X):​c.77C>G​(p.Pro26Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,657 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P26H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: USP9X NM_001039591.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.57
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2766701).

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.77C>G	p.Pro26Arg	missense	Exon 2 of 45	NP_001034680.2	Q93008-1
	USP9X	NM_001410748.1		c.77C>G	p.Pro26Arg	missense	Exon 3 of 46	NP_001397677.1	A0A994J4R6
	USP9X	NM_001039590.3		c.77C>G	p.Pro26Arg	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.77C>G	p.Pro26Arg	missense	Exon 2 of 45	ENSP00000367558.2	Q93008-1
	USP9X	ENST00000703987.1		c.77C>G	p.Pro26Arg	missense	Exon 2 of 45	ENSP00000515604.1	A0A994J4R6
	USP9X	ENST00000324545.9	TSL:5	c.77C>G	p.Pro26Arg	missense	Exon 2 of 45	ENSP00000316357.6	Q93008-3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097657 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 363023

African (AFR) AF: 0.00 AC: 0 AN: 26384

American (AMR) AF: 0.00 AC: 0 AN: 35166

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19359

East Asian (EAS) AF: 0.00 AC: 0 AN: 30173

South Asian (SAS) AF: 0.00 AC: 0 AN: 54055

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40519

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4131

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841788

Other (OTH) AF: 0.00 AC: 0 AN: 46082

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	L
PhyloP100		7.6
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.26
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.058	T
Polyphen		0.27	B
Vest4		0.54
MutPred		0.22		Loss of glycosylation at P26 (P = 0.0342)
MVP		0.36
MPC		0.85
ClinPred		0.90	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.58
gMVP		0.60
Mutation Taster		=81/19	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: rs767741303; hg19: chrX-40982958;