chrX-41123705-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001039591.3(USP9X):c.77C>T(p.Pro26Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000413 in 1,209,457 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 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. P26H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000036 ( 0 hom. 1 hem. )

Consequence

USP9X
NM_001039591.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.57

Publications

2 publications found

Variant links:

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

USP9X links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.25120467).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
USP9X	NM_001039591.3	MANE Select	c.77C>T	p.Pro26Leu	missense	Exon 2 of 45	NP_001034680.2	Q93008-1
USP9X	NM_001410748.1		c.77C>T	p.Pro26Leu	missense	Exon 3 of 46	NP_001397677.1	A0A994J4R6
USP9X	NM_001039590.3		c.77C>T	p.Pro26Leu	missense	Exon 2 of 45	NP_001034679.2	Q93008-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
USP9X	ENST00000378308.7	TSL:5 MANE Select	c.77C>T	p.Pro26Leu	missense	Exon 2 of 45	ENSP00000367558.2	Q93008-1
USP9X	ENST00000703987.1		c.77C>T	p.Pro26Leu	missense	Exon 2 of 45	ENSP00000515604.1	A0A994J4R6
USP9X	ENST00000324545.9	TSL:5	c.77C>T	p.Pro26Leu	missense	Exon 2 of 45	ENSP00000316357.6	Q93008-3

Frequencies

GnomAD3 genomes

AF:

0.00000894

AC:

AN:

111801

Hom.:

Cov.:

show subpopulations

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:

0.000374

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000111

AC:

AN:

179444

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000125

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000364

AC:

AN:

1097656

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363022

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

26384

American (AMR)

AF:

0.00

AC:

AN:

35166

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19359

East Asian (EAS)

AF:

0.00

AC:

AN:

30173

South Asian (SAS)

AF:

0.00

AC:

AN:

54055

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40519

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4131

European-Non Finnish (NFE)

AF:

0.00000238

AC:

AN:

841787

Other (OTH)

AF:

0.0000434

AC:

AN:

46082

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00131091), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.392

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000894

AC:

AN:

111801

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33975

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30721

American (AMR)

AF:

0.00

AC:

AN:

10572

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2647

East Asian (EAS)

AF:

0.00

AC:

AN:

3598

South Asian (SAS)

AF:

0.000374

AC:

AN:

2676

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6016

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53130

Other (OTH)

AF:

0.00

AC:

AN:

1514

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.00000826

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.48

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.25

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

7.6

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-2.2

REVEL

Benign

0.24

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.037

Polyphen

0.0040

Vest4

0.57

MutPred

0.14

Loss of glycosylation at P26 (P = 0.0342)

MVP

0.21

MPC

0.79

ClinPred

0.51

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.45

gMVP

0.55

Mutation Taster

=85/15

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over