NM_001039591.3:c.6084C>T

Variant names:

• chrX-41216651-C-T
• rs146661515
• NM_001039591.3:c.6084C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

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

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

ACMG classification

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039591.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP9X	NM_001039591.3	MANE Select	c.6084C>T	p.Pro2028Pro	splice_region synonymous	Exon 35 of 45	NP_001034680.2	Q93008-1
	USP9X	NM_001410748.1		c.6099C>T	p.Pro2033Pro	splice_region synonymous	Exon 36 of 46	NP_001397677.1	A0A994J4R6
	USP9X	NM_001039590.3		c.6084C>T	p.Pro2028Pro	splice_region synonymous	Exon 35 of 45	NP_001034679.2	Q93008-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP9X	ENST00000378308.7	TSL:5 MANE Select	c.6084C>T	p.Pro2028Pro	splice_region synonymous	Exon 35 of 45	ENSP00000367558.2	Q93008-1
	USP9X	ENST00000703987.1		c.6099C>T	p.Pro2033Pro	splice_region synonymous	Exon 35 of 45	ENSP00000515604.1	A0A994J4R6
	USP9X	ENST00000324545.9	TSL:5	c.6084C>T	p.Pro2028Pro	splice_region synonymous	Exon 35 of 45	ENSP00000316357.6	Q93008-3

Frequencies

GnomAD3 genomes AF: 0.00270 AC: 301 AN: 111467 Hom.: 0 Cov.: 22

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

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.: 22 Cov.: 31 AF XY: 0.00284 AC XY: 1004 AN XY: 354063

African (AFR) AF: 0.000268 AC: 7 AN: 26164

American (AMR) AF: 0.000116 AC: 4 AN: 34405

Ashkenazi Jewish (ASJ) AF: 0.00180 AC: 34 AN: 18909

East Asian (EAS) AF: 0.0000999 AC: 3 AN: 30032

South Asian (SAS) AF: 0.000115 AC: 6 AN: 52305

European-Finnish (FIN) AF: 0.0370 AC: 1480 AN: 40016

Middle Eastern (MID) AF: 0.00123 AC: 5 AN: 4074

European-Non Finnish (NFE) AF: 0.00160 AC: 1338 AN: 835765

Other (OTH) AF: 0.00263 AC: 120 AN: 45641

GnomAD4 genome AF: 0.00270 AC: 301 AN: 111514 Hom.: 0 Cov.: 22 AF XY: 0.00389 AC XY: 131 AN XY: 33710

African (AFR) AF: 0.000195 AC: 6 AN: 30723

American (AMR) AF: 0.0000954 AC: 1 AN: 10486

Ashkenazi Jewish (ASJ) AF: 0.00151 AC: 4 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3597

South Asian (SAS) AF: 0.00 AC: 0 AN: 2627

European-Finnish (FIN) AF: 0.0309 AC: 183 AN: 5929

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00192 AC: 102 AN: 53091

Other (OTH) AF: 0.00329 AC: 5 AN: 1519

Alfa AF: 0.00150 Hom.: 69

Bravo AF: 0.000854

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	1.1
DANN	Benign	0.80
PhyloP100		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Mutation Taster		=44/56	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000094
dbscSNV1_RF	Benign	0.024
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

Other links and lift over

dbSNP: rs146661515; hg19: chrX-41075904; COSMIC: COSV61070865;