rs369178019

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_001039591.3(USP9X):c.4163A>G(p.Asn1388Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000065 in 1,199,715 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 22 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., 5 hem., cov: 23)

Exomes 𝑓: 0.000052 ( 0 hom. 17 hem. )

Consequence

USP9X
NM_001039591.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 8.87

Publications

1 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 -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1453704).

BP6

Variant X-41196668-A-G is Benign according to our data. Variant chrX-41196668-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 520886.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000188 (21/111987) while in subpopulation AMR AF = 0.00133 (14/10508). AF 95% confidence interval is 0.000805. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP9X	NM_001039591.3 link	c.4163A>G	p.Asn1388Ser	missense_variant	Exon 28 of 45	ENST00000378308.7	NP_001034680.2	Q93008-1Q86X58Q6P468

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP9X	ENST00000378308.7 link	c.4163A>G	p.Asn1388Ser	missense_variant	Exon 28 of 45	5	NM_001039591.3	ENSP00000367558.2		Q93008-1

Frequencies

GnomAD3 genomes

AF:

0.000188

AC:

AN:

111987

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000649

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00133

Gnomad ASJ

AF:

0.00113

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000103

AC:

AN:

175441

AF XY:

0.0000647

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000540

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000252

Gnomad OTH exome

AF:

0.000461

GnomAD4 exome

AF:

0.0000524

AC:

AN:

1087728

Hom.:

Cov.:

AF XY:

0.0000481

AC XY:

AN XY:

353670

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26160

American (AMR)

AF:

0.000725

AC:

AN:

34472

Ashkenazi Jewish (ASJ)

AF:

0.000260

AC:

AN:

19262

East Asian (EAS)

AF:

0.00

AC:

AN:

30128

South Asian (SAS)

AF:

0.00

AC:

AN:

52837

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40488

Middle Eastern (MID)

AF:

0.000243

AC:

AN:

4110

European-Non Finnish (NFE)

AF:

0.0000192

AC:

AN:

834496

Other (OTH)

AF:

0.000218

AC:

AN:

45775

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

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:

0.000188

AC:

AN:

111987

Hom.:

Cov.:

AF XY:

0.000146

AC XY:

AN XY:

34147

show subpopulations

African (AFR)

AF:

0.0000649

AC:

AN:

30822

American (AMR)

AF:

0.00133

AC:

AN:

10508

Ashkenazi Jewish (ASJ)

AF:

0.00113

AC:

AN:

2648

East Asian (EAS)

AF:

0.00

AC:

AN:

3605

South Asian (SAS)

AF:

0.00

AC:

AN:

2711

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6028

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000376

AC:

AN:

53223

Other (OTH)

AF:

0.00

AC:

AN:

1515

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000217

Hom.:

Bravo

AF:

0.000416

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000315

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000497

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 06, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Dec 02, 2015

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Intellectual disability, X-linked 99;C4225416:Intellectual disability, X-linked 99, syndromic, female-restricted

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

USP9X-related disorder

Benign:1

Aug 17, 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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.56

DEOGEN2

Benign

0.15

.;T

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

D;D

M_CAP

Benign

0.074

MetaRNN

Benign

0.15

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.4

L;L

PhyloP100

8.9

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.36

N;N

REVEL

Benign

0.15

Sift

Benign

0.41

T;T

Sift4G

Benign

0.41

T;T

Polyphen

0.037

B;B

Vest4

0.55

MVP

0.79

MPC

1.8

ClinPred

0.15

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.19

gMVP

0.24

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over