rs369178019

chrX-41196668-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_001039591.3(USP9X):c.4163A>G(p.Asn1388Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000065 in 1,199,715 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 22 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., 5 hem., cov: 23)
  • Exomes 𝑓: 0.000052 (0 hom. 17 hem.)
• Consequence: USP9X NM_001039591.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 8.87

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 Likely_benign. Variant got -6 ACMG points.

• PP2: Missense variant where missense usually causes diseases, USP9X
• BP4: Computational evidence support a benign effect (MetaRNN=0.1453704).
• BP6: Variant X-41196668-A-G is Benign according to our data. Variant chrX-41196668-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 520886.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, Benign=1}.
• BS2: High Hemizygotes in GnomAd at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USP9X	NM_001039591.3	c.4163A>G	p.Asn1388Ser	missense_variant	28/45	ENST00000378308.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USP9X	ENST00000378308.7	c.4163A>G	p.Asn1388Ser	missense_variant	28/45	5	NM_001039591.3	P4

Frequencies

GnomAD3 genomes AF: 0.000188 AC: 21 AN: 111987 Hom.: 0 Cov.: 23 AF XY: 0.000146 AC XY: 5 AN XY: 34147

Gnomad AFR AF: 0.0000649

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00133

Gnomad ASJ AF: 0.00113

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000376

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000103 AC: 18 AN: 175441 Hom.: 0 AF XY: 0.0000647 AC XY: 4 AN XY: 61803

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000540

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000252

Gnomad OTH exome AF: 0.000461

GnomAD4 exome AF: 0.0000524 AC: 57 AN: 1087728 Hom.: 0 Cov.: 28 AF XY: 0.0000481 AC XY: 17 AN XY: 353670

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000725

Gnomad4 ASJ exome AF: 0.000260

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000192

Gnomad4 OTH exome AF: 0.000218

GnomAD4 genome AF: 0.000188 AC: 21 AN: 111987 Hom.: 0 Cov.: 23 AF XY: 0.000146 AC XY: 5 AN XY: 34147

Gnomad4 AFR AF: 0.0000649

Gnomad4 AMR AF: 0.00133

Gnomad4 ASJ AF: 0.00113

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000376

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000217 Hom.: 2

Bravo AF: 0.000416

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000315 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000497 AC: 6

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 06, 2021	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 02, 2015

- -

Intellectual disability, X-linked 99;C4225416:Intellectual disability, X-linked 99, syndromic, female-restricted Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

USP9X-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 17, 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	0.081
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	21
Dann	Benign	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.36	N;N
REVEL	Benign	0.15
Sift	Benign	0.41	T;T
Sift4G	Benign	0.41	T;T
Polyphen		0.037	B;B
Vest4		0.55
MVP		0.79
MPC		1.8
ClinPred		0.15	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs369178019; hg19: chrX-41055921;