Genetic Variant USP9X:p.Ile1974Val (chrX-41216487-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001039591.3(USP9X):c.5920A>G(p.Ile1974Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000942 in 1,209,575 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 39 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., 3 hem., cov: 22)

Exomes 𝑓: 0.000098 ( 0 hom. 36 hem. )

Consequence

USP9X
NM_001039591.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.183

Publications

0 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0063857436).

BP6

Variant X-41216487-A-G is Benign according to our data. Variant chrX-41216487-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 599442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000539 (6/111327) while in subpopulation SAS AF = 0.000761 (2/2629). AF 95% confidence interval is 0.000135. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

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
USP9X	NM_001039591.3	MANE Select	c.5920A>G	p.Ile1974Val	missense	Exon 35 of 45	NP_001034680.2
USP9X	NM_001410748.1		c.5935A>G	p.Ile1979Val	missense	Exon 36 of 46	NP_001397677.1
USP9X	NM_001039590.3		c.5920A>G	p.Ile1974Val	missense	Exon 35 of 45	NP_001034679.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
USP9X	ENST00000378308.7	TSL:5 MANE Select	c.5920A>G	p.Ile1974Val	missense	Exon 35 of 45	ENSP00000367558.2
USP9X	ENST00000703987.1		c.5935A>G	p.Ile1979Val	missense	Exon 35 of 45	ENSP00000515604.1
USP9X	ENST00000324545.9	TSL:5	c.5920A>G	p.Ile1974Val	missense	Exon 35 of 45	ENSP00000316357.6

Frequencies

GnomAD3 genomes

AF:

0.0000539

AC:

AN:

111275

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000327

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000192

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000759

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00417

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000285

AC:

AN:

182163

AF XY:

0.000266

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00128

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000728

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000368

Gnomad OTH exome

AF:

0.000224

GnomAD4 exome

AF:

0.0000983

AC:

108

AN:

1098248

Hom.:

Cov.:

AF XY:

0.0000990

AC XY:

AN XY:

363604

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26402

American (AMR)

AF:

0.00131

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19383

East Asian (EAS)

AF:

0.0000662

AC:

AN:

30205

South Asian (SAS)

AF:

0.000591

AC:

AN:

54149

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40532

Middle Eastern (MID)

AF:

0.00193

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.0000131

AC:

AN:

842136

Other (OTH)

AF:

0.000174

AC:

AN:

46097

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.0000539

AC:

AN:

111327

Hom.:

Cov.:

AF XY:

0.0000896

AC XY:

AN XY:

33483

show subpopulations

African (AFR)

AF:

0.0000327

AC:

AN:

30620

American (AMR)

AF:

0.000191

AC:

AN:

10450

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2640

East Asian (EAS)

AF:

0.00

AC:

AN:

3547

South Asian (SAS)

AF:

0.000761

AC:

AN:

2629

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5978

Middle Eastern (MID)

AF:

0.00459

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53051

Other (OTH)

AF:

0.00

AC:

AN:

1509

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Hom

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:

0.000142

Hom.:

Bravo

AF:

0.000166

ExAC

AF:

0.000322

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Dec 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 11, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

USP9X: BP4, BS2

not specified

Benign:1

Nov 20, 2017

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1, BS2, BP4, BP5; This alteration has an allele frequency that is greater than expected for the associated disease, was seen in a healthy adult where full penetrance of the disorder is expected at an early age, is predicted to be tolerated by multiple functional prediction tools, and was found in a case with an alternate molecular basis for disease.

Inborn genetic diseases

Benign:1

Feb 06, 2025

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

USP9X-related disorder

Benign:1

May 23, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.87

BayesDel_noAF

Benign

-1.1

CADD

Benign

0.11

(source)

DANN

Benign

0.42

DEOGEN2

Benign

0.18

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.77

M_CAP

Benign

0.010

MetaRNN

Benign

0.0064

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.0

PhyloP100

-0.18

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.62

REVEL

Benign

0.037

Sift

Benign

0.21

Sift4G

Benign

0.39

Polyphen

0.0

Vest4

0.043

MutPred

0.37

Gain of catalytic residue at I1974 (P = 0.0788)

MVP

0.11

MPC

0.77

ClinPred

0.010

GERP RS

-3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.086

gMVP

0.32

Mutation Taster

=100/0

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

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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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over