X-41229781-TA-TAA

Variant names:

• chrX-41229781-T-TA
• rs774054468
• NM_001039591.3:c.7431+9dupA

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 8P and 4B. PVS1 BS2

The NM_001410748.1(USP9X):​c.7455dupA​(p.Ala2486SerfsTer17) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. A2486A) has been classified as Likely benign. 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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8 O:1
• Conservation: PhyloP100: 6.93
• Publications: 5 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: Uncertain_significance. The variant received 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001410748.1. 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.7431+9dupA		intron	N/A	NP_001034680.2	Q93008-1
	USP9X	NM_001410748.1		c.7455dupA	p.Ala2486SerfsTer17	frameshift	Exon 44 of 46	NP_001397677.1	A0A994J4R6
	USP9X	NM_001039590.3		c.7440dupA	p.Ala2481SerfsTer17	frameshift	Exon 43 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.7431+9dupA		intron	N/A	ENSP00000367558.2	Q93008-1
	USP9X	ENST00000703987.1		c.7455dupA	p.Ala2486SerfsTer17	frameshift	Exon 43 of 45	ENSP00000515604.1	A0A994J4R6
	USP9X	ENST00000324545.9	TSL:5	c.7440dupA	p.Ala2481SerfsTer17	frameshift	Exon 43 of 45	ENSP00000316357.6	Q93008-3

Frequencies

GnomAD3 genomes AF: 0.0000446 AC: 5 AN: 112162 Hom.: 0 Cov.: 24

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

GnomAD2 exomes AF: 0.0000661 AC: 12 AN: 181666 AF XY: 0.0000601

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 FIN exome AF: 0.0000626

Gnomad NFE exome AF: 0.0000986

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000519 AC: 57 AN: 1097810 Hom.: 0 Cov.: 31 AF XY: 0.0000523 AC XY: 19 AN XY: 363200

African (AFR) AF: 0.00 AC: 0 AN: 26378

American (AMR) AF: 0.0000285 AC: 1 AN: 35135

Ashkenazi Jewish (ASJ) AF: 0.0000516 AC: 1 AN: 19362

East Asian (EAS) AF: 0.0000662 AC: 2 AN: 30199

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54020

European-Finnish (FIN) AF: 0.0000494 AC: 2 AN: 40525

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4131

European-Non Finnish (NFE) AF: 0.0000594 AC: 50 AN: 841988

Other (OTH) AF: 0.00 AC: 0 AN: 46072

GnomAD4 genome AF: 0.0000446 AC: 5 AN: 112215 Hom.: 0 Cov.: 24 AF XY: 0.0000291 AC XY: 1 AN XY: 34417

African (AFR) AF: 0.00 AC: 0 AN: 30961

American (AMR) AF: 0.0000946 AC: 1 AN: 10567

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3615

South Asian (SAS) AF: 0.00 AC: 0 AN: 2746

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6066

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.0000752 AC: 4 AN: 53171

Other (OTH) AF: 0.00 AC: 0 AN: 1539

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

EpiCase AF: 0.000110

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	2	-	not specified (2)
-	1	-	Intellectual disability, X-linked 99 (1)
-	1	-	Intellectual disability, X-linked 99;C4225416:Intellectual disability, X-linked 99, syndromic, female-restricted (1)
-	1	-	USP9X-related disorder (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.9
Mutation Taster		=133/67	disease causing (ClinVar)

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

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

Other links and lift over

dbSNP: rs774054468;

hg19: chrX-41089034;

COSMIC: COSV61066779;