NM_001039591.3:c.10A>G

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_001039591.3(USP9X):c.10A>G(p.Thr4Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,209,688 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000010 ( 0 hom. 3 hem. )

Consequence

USP9X
NM_001039591.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.87

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 Likely_benign. Variant got -5 ACMG points.

PP2

Missense variant in the USP9X gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 24 curated pathogenic missense variants (we use a threshold of 10). The gene has 36 curated benign missense variants. Gene score misZ: 6.4105 (above the threshold of 3.09). GenCC associations: The gene is linked to 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=0.1865552).

BS2

High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP9X	NM_001039591.3 link	c.10A>G	p.Thr4Ala	missense_variant	Exon 2 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.10A>G	p.Thr4Ala	missense_variant	Exon 2 of 45	5	NM_001039591.3	ENSP00000367558.2		Q93008-1

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112189

Hom.:

Cov.:

AF XY:

0.0000291

AC XY:

AN XY:

34331

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000941

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000445

AC:

AN:

179726

Hom.:

AF XY:

0.0000152

AC XY:

AN XY:

65644

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000220

Gnomad ASJ exome

AF:

0.000269

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000100

AC:

AN:

1097499

Hom.:

Cov.:

AF XY:

0.00000827

AC XY:

AN XY:

362873

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000142

Gnomad4 ASJ exome

AF:

0.000103

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000356

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.0000178

AC:

AN:

112189

Hom.:

Cov.:

AF XY:

0.0000291

AC XY:

AN XY:

34331

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000941

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.00000826

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Feb 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 4 of the USP9X protein (p.Thr4Ala). This variant is present in population databases (rs775400408, gnomAD 0.03%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with autism spectrum disorder (PMID: 33023636). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬¨‚Ä†is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.43

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.17

.;T

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.64

T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.19

T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.46

N;N

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.54

N;N

REVEL

Uncertain

0.36

Sift

Benign

0.49

T;T

Sift4G

Benign

0.47

T;T

Polyphen

0.0

B;B

Vest4

0.52

MutPred

0.15

Loss of glycosylation at T4 (P = 0.0242);Loss of glycosylation at T4 (P = 0.0242);

MVP

0.77

MPC

0.77

ClinPred

0.13

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.26

gMVP

0.49

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