rs760867179

chrX-41216487-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_001039591.3(USP9X):c.5920A>G(p.Ile1974Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000942 in 1,209,575 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 39 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000054 (0 hom., 3 hem., cov: 22)
  • Exomes 𝑓: 0.000098 (0 hom. 36 hem.)
• Consequence: USP9X NM_001039591.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.183

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, USP9X
• BP4: Computational evidence support a benign effect (MetaRNN=0.0063857436).
• BP6: Variant X-41216487-A-G is Benign according to our data. Variant chrX-41216487-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 599442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41216487-A-G is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USP9X	NM_001039591.3	c.5920A>G	p.Ile1974Val	missense_variant	35/45	ENST00000378308.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USP9X	ENST00000378308.7	c.5920A>G	p.Ile1974Val	missense_variant	35/45	5	NM_001039591.3	P4

Frequencies

GnomAD3 genomes AF: 0.0000539 AC: 6 AN: 111275 Hom.: 0 Cov.: 22 AF XY: 0.0000898 AC XY: 3 AN XY: 33421

Gnomad AFR AF: 0.0000327

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000192

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000759

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00417

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000285 AC: 52 AN: 182163 Hom.: 0 AF XY: 0.000266 AC XY: 18 AN XY: 67681

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00128

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000728

Gnomad SAS exome AF: 0.000629

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000368

Gnomad OTH exome AF: 0.000224

GnomAD4 exome AF: 0.0000983 AC: 108 AN: 1098248 Hom.: 0 Cov.: 32 AF XY: 0.0000990 AC XY: 36 AN XY: 363604

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.00131

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000662

Gnomad4 SAS exome AF: 0.000591

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000131

Gnomad4 OTH exome AF: 0.000174

GnomAD4 genome AF: 0.0000539 AC: 6 AN: 111327 Hom.: 0 Cov.: 22 AF XY: 0.0000896 AC XY: 3 AN XY: 33483

Gnomad4 AFR AF: 0.0000327

Gnomad4 AMR AF: 0.000191

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000761

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 1

Bravo AF: 0.000166

ExAC AF: 0.000322 AC: 39

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 11, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 13, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Nov 20, 2017

BS1, BS2, BP4, BP5; This alteration has an allele frequency that is greater than expected for the associated disease, was seen in a healthy adult where full penetrance of the disorder is expected at an early age, is predicted to be tolerated by multiple functional prediction tools, and was found in a case with an alternate molecular basis for disease. -

USP9X-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 23, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.87	T
BayesDel_noAF	Benign	-1.1
Cadd	Benign	0.11
Dann	Benign	0.42
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.0064	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.0	L;L
MutationTaster	Benign	0.71	D;D
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.62	N;N
REVEL	Benign	0.037
Sift	Benign	0.21	T;T
Sift4G	Benign	0.39	T;T
Polyphen		0.0	B;B
Vest4		0.043
MutPred		0.37		Gain of catalytic residue at I1974 (P = 0.0788);Gain of catalytic residue at I1974 (P = 0.0788);
MVP		0.11
MPC		0.77
ClinPred		0.010	T
GERP RS		-3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.086
gMVP		0.32

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

Publications

LitVar

Other links and lift over

dbSNP: rs760867179; hg19: chrX-41075740; COSMIC: COSV61077112;