X-41216651-C-T

Position:

• chrX-41216651-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001039591.3(USP9X):​c.6084C>T​(p.Pro2028Pro) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00275 in 1,198,825 control chromosomes in the GnomAD database, including 22 homozygotes. There are 1,135 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (0 hom., 131 hem., cov: 22)
  • Exomes 𝑓: 0.0028 (22 hom. 1004 hem.)
• Consequence: USP9X NM_001039591.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.00009426
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.51

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant X-41216651-C-T is Benign according to our data. Variant chrX-41216651-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 377155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41216651-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=3.51 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0027 (301/111514) while in subpopulation NFE AF= 0.00192 (102/53091). AF 95% confidence interval is 0.00162. There are 0 homozygotes in gnomad4. There are 131 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 131 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP9X	NM_001039591.3	c.6084C>T	p.Pro2028Pro	splice_region_variant, synonymous_variant	35/45	ENST00000378308.7	NP_001034680.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP9X	ENST00000378308.7	c.6084C>T	p.Pro2028Pro	splice_region_variant, synonymous_variant	35/45	5	NM_001039591.3	ENSP00000367558.2

Frequencies

GnomAD3 genomes AF: 0.00270 AC: 301 AN: 111467 Hom.: 0 Cov.: 22 AF XY: 0.00389 AC XY: 131 AN XY: 33653

Gnomad AFR AF: 0.000196

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000955

Gnomad ASJ AF: 0.00151

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0309

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00192

Gnomad OTH AF: 0.00333

GnomAD3 exomes AF: 0.00420 AC: 710 AN: 169079 Hom.: 4 AF XY: 0.00395 AC XY: 228 AN XY: 57775

Gnomad AFR exome AF: 0.000331

Gnomad AMR exome AF: 0.0000762

Gnomad ASJ exome AF: 0.00195

Gnomad EAS exome AF: 0.0000751

Gnomad SAS exome AF: 0.000182

Gnomad FIN exome AF: 0.0324

Gnomad NFE exome AF: 0.00217

Gnomad OTH exome AF: 0.00697

GnomAD4 exome AF: 0.00276 AC: 2997 AN: 1087311 Hom.: 22 Cov.: 31 AF XY: 0.00284 AC XY: 1004 AN XY: 354063

Gnomad4 AFR exome AF: 0.000268

Gnomad4 AMR exome AF: 0.000116

Gnomad4 ASJ exome AF: 0.00180

Gnomad4 EAS exome AF: 0.0000999

Gnomad4 SAS exome AF: 0.000115

Gnomad4 FIN exome AF: 0.0370

Gnomad4 NFE exome AF: 0.00160

Gnomad4 OTH exome AF: 0.00263

GnomAD4 genome AF: 0.00270 AC: 301 AN: 111514 Hom.: 0 Cov.: 22 AF XY: 0.00389 AC XY: 131 AN XY: 33710

Gnomad4 AFR AF: 0.000195

Gnomad4 AMR AF: 0.0000954

Gnomad4 ASJ AF: 0.00151

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0309

Gnomad4 NFE AF: 0.00192

Gnomad4 OTH AF: 0.00329

Alfa AF: 0.00162 Hom.: 69

Bravo AF: 0.000854

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 30, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 15, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 24, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	1.1
DANN	Benign	0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000094
dbscSNV1_RF	Benign	0.024
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: rs146661515; hg19: chrX-41075904; COSMIC: COSV61070865;