Variant X-41229781-T-TA details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 8P and 4B. PVS1BS2

The NM_001410748.1(USP9X):c.7455dupA(p.Ala2486fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000512 in 1,210,025 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 20 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.000052 ( 0 hom. 19 hem. )

Consequence

USP9X
NM_001410748.1 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8O:1

Conservation

PhyloP100: 6.93

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:

USP9X (HGNC:):

USP9X links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

BS2

High Hemizygotes in GnomAdExome4 at 19 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP9X	NM_001039591.3 linkuse as main transcript	c.7431+9dupA		intron_variant		ENST00000378308.7	NP_001034680.2	Q93008-1Q86X58Q6P468

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP9X	ENST00000378308.7 linkuse as main transcript	c.7431+9dupA		intron_variant		5	NM_001039591.3	ENSP00000367558.2		Q93008-1

Frequencies

GnomAD3 genomes

AF:

0.0000446

AC:

AN:

112162

Hom.:

Cov.:

AF XY:

0.0000291

AC XY:

AN XY:

34354

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000948

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000752

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000661

AC:

AN:

181666

Hom.:

AF XY:

0.0000601

AC XY:

AN XY:

66552

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000736

Gnomad ASJ exome

AF:

0.000135

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000626

Gnomad NFE exome

AF:

0.0000986

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000519

AC:

AN:

1097810

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

363200

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000285

Gnomad4 ASJ exome

AF:

0.0000516

Gnomad4 EAS exome

AF:

0.0000662

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.0000494

Gnomad4 NFE exome

AF:

0.0000594

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000446

AC:

AN:

112215

Hom.:

Cov.:

AF XY:

0.0000291

AC XY:

AN XY:

34417

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000946

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000752

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

EpiCase

AF:

0.000110

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 14, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 23, 2021	Identified as a maternally inherited variant in five hemizygous males with neurodevelopmental disorders from three unrelated families in the literature (Johnson et al., 2019), and in one family, the mother reportedly had seizures in childhood which resolved; Of the two isoforms of the USP9X gene, the long isoform is poorly expressed in male control fibroblasts compared to the short isoform, and this variant is located within exon 43 of the long isoform and within intron 43 of the short isoform (Johnson et al., 2019); Expression studies using patient-derived fibroblasts show that this variant causes loss of only the long isoform while overall levels of USP9X mRNA and protein remain similar to controls, suggesting USP9X mRNA and protein are still normally expressed from the short isoform (Johnson et al., 2019); however, further studies are needed to determine the clinical relevance of the long isoform and the role of differential isoform expression in gene function; Frameshift variant predicted to result in protein truncation or nonsense mediated decay for which loss-of-function in only the long isoform of the USP9X gene is not a known mechanism of disease; This variant is associated with the following publications: (PMID: 27770309, 31443933) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 18, 2023	This sequence change creates a premature translational stop signal (p.Ala2481Serfs*17) in the USP9X gene. However, it is currently unclear if variants that occur in this region of the gene cause disease. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in 5 males with neurodevelopmental disorders (PMID: 31443933, Invitae). ClinVar contains an entry for this variant (Variation ID: 423784). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 03, 2016	- -

USP9X-related disorder

Uncertain:1Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 19, 2022	The USP9X c.7440dupA variant is predicted to result in a frameshift and premature protein termination (p.Ala2481Serfs*17). This variant has been previously reported as maternally inherited and a variant of uncertain significance in three individuals with neurodevelopmental disorder (Table S4, Johnson et al. 2020. PubMed ID: 31443933). This variant is reported in 0.013% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, including four hemizygous alleles (http://gnomad.broadinstitute.org/variant/X-41089034-T-TA). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Uncertain significance and reported on 06-15-2020 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Intellectual disability, X-linked 99

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 30, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 16, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.25

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.25

Position offset: 46

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