X-41216651-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001039591.3(USP9X):c.6084C>T(p.Pro2028Pro) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00275 in 1,198,825 control chromosomes in the GnomAD database, including 22 homozygotes. There are 1,135 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0027 ( 0 hom., 131 hem., cov: 22)

Exomes 𝑓: 0.0028 ( 22 hom. 1004 hem. )

Consequence

USP9X
NM_001039591.3 splice_region, synonymous

Scores

Splicing: ADA: 0.00009426

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.51

Publications

4 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant X-41216651-C-T is Benign according to our data. Variant chrX-41216651-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=3.51 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0027 (301/111514) while in subpopulation NFE AF = 0.00192 (102/53091). AF 95% confidence interval is 0.00162. There are 0 homozygotes in GnomAd4. There are 131 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 131 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP9X	NM_001039591.3 link	c.6084C>T	p.Pro2028Pro	splice_region_variant, synonymous_variant	Exon 35 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.6084C>T	p.Pro2028Pro	splice_region_variant, synonymous_variant	Exon 35 of 45	5	NM_001039591.3	ENSP00000367558.2		Q93008-1

Frequencies

GnomAD3 genomes

AF:

0.00270

AC:

301

AN:

111467

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000196

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000955

Gnomad ASJ

AF:

0.00151

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0309

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00192

Gnomad OTH

AF:

0.00333

GnomAD2 exomes

AF:

0.00420

AC:

710

AN:

169079

AF XY:

0.00395

show subpopulations

Gnomad AFR exome

AF:

0.000331

Gnomad AMR exome

AF:

0.0000762

Gnomad ASJ exome

AF:

0.00195

Gnomad EAS exome

AF:

0.0000751

Gnomad FIN exome

AF:

0.0324

Gnomad NFE exome

AF:

0.00217

Gnomad OTH exome

AF:

0.00697

GnomAD4 exome

AF:

0.00276

AC:

2997

AN:

1087311

Hom.:

Cov.:

AF XY:

0.00284

AC XY:

1004

AN XY:

354063

show subpopulations

African (AFR)

AF:

0.000268

AC:

AN:

26164

American (AMR)

AF:

0.000116

AC:

AN:

34405

Ashkenazi Jewish (ASJ)

AF:

0.00180

AC:

AN:

18909

East Asian (EAS)

AF:

0.0000999

AC:

AN:

30032

South Asian (SAS)

AF:

0.000115

AC:

AN:

52305

European-Finnish (FIN)

AF:

0.0370

AC:

1480

AN:

40016

Middle Eastern (MID)

AF:

0.00123

AC:

AN:

4074

European-Non Finnish (NFE)

AF:

0.00160

AC:

1338

AN:

835765

Other (OTH)

AF:

0.00263

AC:

120

AN:

45641

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

103

205

308

410

513

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<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:

0.00270

AC:

301

AN:

111514

Hom.:

Cov.:

AF XY:

0.00389

AC XY:

131

AN XY:

33710

show subpopulations

African (AFR)

AF:

0.000195

AC:

AN:

30723

American (AMR)

AF:

0.0000954

AC:

AN:

10486

Ashkenazi Jewish (ASJ)

AF:

0.00151

AC:

AN:

2642

East Asian (EAS)

AF:

0.00

AC:

AN:

3597

South Asian (SAS)

AF:

0.00

AC:

AN:

2627

European-Finnish (FIN)

AF:

0.0309

AC:

183

AN:

5929

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00192

AC:

102

AN:

53091

Other (OTH)

AF:

0.00329

AC:

AN:

1519

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

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:

0.00150

Hom.:

Bravo

AF:

0.000854

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided