rs878853105

Variant names:

• chrX-41137008-C-G
• rs878853105
• NM_001039591.3:c.640C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001039591.3(USP9X):​c.640C>G​(p.Pro214Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,208,609 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P214L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000013 (0 hom. 3 hem.)
• Consequence: USP9X NM_001039591.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.57
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.37151378).
• BS2: High Hemizygotes in GnomAdExome4 at 3 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.640C>G	p.Pro214Ala	missense	Exon 6 of 45	NP_001034680.2	Q93008-1
	USP9X	NM_001410748.1		c.640C>G	p.Pro214Ala	missense	Exon 7 of 46	NP_001397677.1	A0A994J4R6
	USP9X	NM_001039590.3		c.640C>G	p.Pro214Ala	missense	Exon 6 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.640C>G	p.Pro214Ala	missense	Exon 6 of 45	ENSP00000367558.2	Q93008-1
	USP9X	ENST00000703987.1		c.640C>G	p.Pro214Ala	missense	Exon 6 of 45	ENSP00000515604.1	A0A994J4R6
	USP9X	ENST00000324545.9	TSL:5	c.640C>G	p.Pro214Ala	missense	Exon 6 of 45	ENSP00000316357.6	Q93008-3

Frequencies

GnomAD3 genomes AF: 0.00000892 AC: 1 AN: 112101 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000128 AC: 14 AN: 1096508 Hom.: 0 Cov.: 29 AF XY: 0.00000829 AC XY: 3 AN XY: 361910

African (AFR) AF: 0.00 AC: 0 AN: 26370

American (AMR) AF: 0.00 AC: 0 AN: 35177

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19355

East Asian (EAS) AF: 0.00 AC: 0 AN: 30157

South Asian (SAS) AF: 0.00 AC: 0 AN: 54004

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40497

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4133

European-Non Finnish (NFE) AF: 0.0000155 AC: 13 AN: 840780

Other (OTH) AF: 0.0000217 AC: 1 AN: 46035

GnomAD4 genome AF: 0.00000892 AC: 1 AN: 112101 Hom.: 0 Cov.: 23 AF XY: 0.0000292 AC XY: 1 AN XY: 34251

African (AFR) AF: 0.00 AC: 0 AN: 30838

American (AMR) AF: 0.00 AC: 0 AN: 10566

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3599

South Asian (SAS) AF: 0.00 AC: 0 AN: 2718

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53226

Other (OTH) AF: 0.00 AC: 0 AN: 1514

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.33	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.81	L
PhyloP100		7.6
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.23
Sift	Benign	0.32	T
Sift4G	Benign	0.39	T
Polyphen		0.016	B
Vest4		0.58
MutPred		0.17		Loss of glycosylation at P214 (P = 0.0404)
MVP		0.42
MPC		0.79
ClinPred		0.69	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.35
gMVP		0.58
Mutation Taster		=45/55	disease causing

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: rs878853105; hg19: chrX-40996261;