rs10463

Variant names:

• chrX-41232688-A-G
• rs10463
• NM_001039591.3:c.*164A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001039591.3(USP9X):​c.*164A>G variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.0816 in 636,648 control chromosomes in the GnomAD database, including 1,707 homozygotes. There are 13,354 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (216 hom., 1898 hem., cov: 23)
  • Exomes 𝑓: 0.086 (1491 hom. 11456 hem.)
• Consequence: USP9X NM_001039591.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.34
• Publications: 8 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant X-41232688-A-G is Benign according to our data. Variant chrX-41232688-A-G is described in ClinVar as Benign. ClinVar VariationId is 1296676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0904 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP9X	NM_001039591.3	c.*164A>G		3_prime_UTR_variant	Exon 45 of 45	ENST00000378308.7	NP_001034680.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP9X	ENST00000378308.7	c.*164A>G		3_prime_UTR_variant	Exon 45 of 45	5	NM_001039591.3	ENSP00000367558.2

Frequencies

GnomAD3 genomes AF: 0.0603 AC: 6755 AN: 111941 Hom.: 216 Cov.: 23

Gnomad AFR AF: 0.0124

Gnomad AMI AF: 0.161

Gnomad AMR AF: 0.0440

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.000550

Gnomad SAS AF: 0.0427

Gnomad FIN AF: 0.0561

Gnomad MID AF: 0.118

Gnomad NFE AF: 0.0925

Gnomad OTH AF: 0.0539

GnomAD4 exome AF: 0.0862 AC: 45220 AN: 524658 Hom.: 1491 Cov.: 8 AF XY: 0.0992 AC XY: 11456 AN XY: 115458

African (AFR) AF: 0.0126 AC: 168 AN: 13301

American (AMR) AF: 0.0382 AC: 538 AN: 14099

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 1174 AN: 10385

East Asian (EAS) AF: 0.000129 AC: 3 AN: 23258

South Asian (SAS) AF: 0.0696 AC: 1674 AN: 24060

European-Finnish (FIN) AF: 0.0644 AC: 1961 AN: 30438

Middle Eastern (MID) AF: 0.124 AC: 328 AN: 2645

European-Non Finnish (NFE) AF: 0.0982 AC: 37384 AN: 380869

Other (OTH) AF: 0.0777 AC: 1990 AN: 25603

GnomAD4 genome AF: 0.0603 AC: 6755 AN: 111990 Hom.: 216 Cov.: 23 AF XY: 0.0555 AC XY: 1898 AN XY: 34176

African (AFR) AF: 0.0124 AC: 382 AN: 30923

American (AMR) AF: 0.0440 AC: 463 AN: 10527

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 320 AN: 2630

East Asian (EAS) AF: 0.000552 AC: 2 AN: 3625

South Asian (SAS) AF: 0.0439 AC: 120 AN: 2731

European-Finnish (FIN) AF: 0.0561 AC: 338 AN: 6023

Middle Eastern (MID) AF: 0.125 AC: 27 AN: 216

European-Non Finnish (NFE) AF: 0.0925 AC: 4914 AN: 53117

Other (OTH) AF: 0.0526 AC: 80 AN: 1522

Alfa AF: 0.0737 Hom.: 4034

Bravo AF: 0.0557

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 04, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	12
DANN	Benign	0.91
PhyloP100		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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

Other links and lift over

dbSNP: rs10463; hg19: chrX-41091941;