rs55900117

Variant names:

• chrX-41198769-A-G
• rs55900117
• NM_001039591.3:c.4603+19A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001039591.3(USP9X):​c.4603+19A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0124 in 1,128,223 control chromosomes in the GnomAD database, including 67 homozygotes. There are 4,105 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0076 (6 hom., 224 hem., cov: 24)
  • Exomes 𝑓: 0.013 (61 hom. 3881 hem.)
• Consequence: USP9X NM_001039591.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.234
• Publications: 1 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, G2P, Labcorp Genetics (formerly Invitae)
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant X-41198769-A-G is Benign according to our data. Variant chrX-41198769-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00762 (862/113154) while in subpopulation NFE AF = 0.0134 (717/53420). AF 95% confidence interval is 0.0126. There are 6 homozygotes in GnomAd4. There are 224 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.4603+19A>G		intron	N/A	NP_001034680.2	Q93008-1
	USP9X	NM_001410748.1		c.4618+19A>G		intron	N/A	NP_001397677.1	A0A994J4R6
	USP9X	NM_001039590.3		c.4603+19A>G		intron	N/A	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.4603+19A>G		intron	N/A	ENSP00000367558.2	Q93008-1
	USP9X	ENST00000703987.1		c.4618+19A>G		intron	N/A	ENSP00000515604.1	A0A994J4R6
	USP9X	ENST00000324545.9	TSL:5	c.4603+19A>G		intron	N/A	ENSP00000316357.6	Q93008-3

Frequencies

GnomAD3 genomes AF: 0.00764 AC: 864 AN: 113099 Hom.: 6 Cov.: 24

Gnomad AFR AF: 0.00212

Gnomad AMI AF: 0.00290

Gnomad AMR AF: 0.00346

Gnomad ASJ AF: 0.00263

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00423

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0134

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00742 AC: 1044 AN: 140636 AF XY: 0.00744

Gnomad AFR exome AF: 0.00207

Gnomad AMR exome AF: 0.00340

Gnomad ASJ exome AF: 0.00175

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00183

Gnomad NFE exome AF: 0.0135

Gnomad OTH exome AF: 0.00672

GnomAD4 exome AF: 0.0129 AC: 13105 AN: 1015069 Hom.: 61 Cov.: 19 AF XY: 0.0132 AC XY: 3881 AN XY: 294365

African (AFR) AF: 0.00196 AC: 48 AN: 24439

American (AMR) AF: 0.00327 AC: 104 AN: 31767

Ashkenazi Jewish (ASJ) AF: 0.00208 AC: 38 AN: 18284

East Asian (EAS) AF: 0.00 AC: 0 AN: 28771

South Asian (SAS) AF: 0.00460 AC: 223 AN: 48447

European-Finnish (FIN) AF: 0.00200 AC: 78 AN: 38980

Middle Eastern (MID) AF: 0.00225 AC: 8 AN: 3562

European-Non Finnish (NFE) AF: 0.0157 AC: 12174 AN: 777666

Other (OTH) AF: 0.0100 AC: 432 AN: 43153

GnomAD4 genome AF: 0.00762 AC: 862 AN: 113154 Hom.: 6 Cov.: 24 AF XY: 0.00635 AC XY: 224 AN XY: 35302

African (AFR) AF: 0.00211 AC: 66 AN: 31245

American (AMR) AF: 0.00345 AC: 37 AN: 10721

Ashkenazi Jewish (ASJ) AF: 0.00263 AC: 7 AN: 2664

East Asian (EAS) AF: 0.00 AC: 0 AN: 3634

South Asian (SAS) AF: 0.00389 AC: 11 AN: 2830

European-Finnish (FIN) AF: 0.00113 AC: 7 AN: 6188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.0134 AC: 717 AN: 53420

Other (OTH) AF: 0.00972 AC: 15 AN: 1543

Alfa AF: 0.00941 Hom.: 85

Bravo AF: 0.00744

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.38
DANN	Benign	0.71
PhyloP100		0.23
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs55900117;

hg19: chrX-41058022;

COSMIC: COSV61069618;