rs760867179

Positions:

chrX-41216487-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

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. 14/20 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:4

Conservation

PhyloP100: -0.183

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), USP9X. . Gene score misZ 6.4105 (greater than the threshold 3.09). GenCC has associacion of gene with non-syndromic X-linked intellectual disability, X-linked syndromic intellectual disability, intellectual disability, X-linked 99, syndromic, female-restricted, intellectual disability, X-linked 99, X-linked female restricted facial dysmorphism-short stature-choanal atresia-intellectual disability.

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 [Likely_benign]. Clinvar id is 599442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41216487-A-G is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP9X	NM_001039591.3 linkuse as main transcript	c.5920A>G	p.Ile1974Val	missense_variant	35/45	ENST00000378308.7	NP_001034680.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP9X	ENST00000378308.7 linkuse as main transcript	c.5920A>G	p.Ile1974Val	missense_variant	35/45	5	NM_001039591.3	ENSP00000367558	P4	Q93008-1

Frequencies

GnomAD3 genomes

AF:

0.0000539

AC:

AN:

111275

Hom.:

Cov.:

AF XY:

0.0000898

AC XY:

AN XY:

33421

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

GnomAD3 exomes

AF:

0.000285

AC:

AN:

182163

Hom.:

AF XY:

0.000266

AC XY:

AN XY:

67681

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 SAS exome

AF:

0.000629

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

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.00131

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000662

Gnomad4 SAS exome

AF:

0.000591

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000131

Gnomad4 OTH exome

AF:

0.000174

GnomAD4 genome

AF:

0.0000539

AC:

AN:

111327

Hom.:

Cov.:

AF XY:

0.0000896

AC XY:

AN XY:

33483

show subpopulations

Gnomad4 AFR

AF:

0.0000327

Gnomad4 AMR

AF:

0.000191

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000761

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

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:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 13, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 11, 2021	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Nov 20, 2017

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. -

USP9X-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 23, 2022

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

0.069

BayesDel_addAF

Benign

-0.87

BayesDel_noAF

Benign

-1.1

CADD

Benign

0.11

DANN

Benign

0.42

DEOGEN2

Benign

0.18

.;T

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.77

T;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.0064

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.0

L;L

MutationTaster

Benign

0.71

D;D

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.62

N;N

REVEL

Benign

0.037

Sift

Benign

0.21

T;T

Sift4G

Benign

0.39

T;T

Polyphen

0.0

B;B

Vest4

0.043

MutPred

0.37

Gain of catalytic residue at I1974 (P = 0.0788);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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over