rs1555920902

Variant names:

• chrX-41141106-A-T
• rs1555920902
• NM_001039591.3:c.911A>T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_001039591.3(USP9X):​c.911A>T​(p.Asn304Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: USP9X NM_001039591.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.95

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the USP9X gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 24 curated pathogenic missense variants (we use a threshold of 10). The gene has 36 curated benign missense variants. Gene score misZ: 6.4105 (above the threshold of 3.09). GenCC associations: The gene is linked to non-syndromic X-linked intellectual disability, X-linked syndromic intellectual disability, intellectual disability, X-linked 99, syndromic, female-restricted, intellectual disability, X-linked 99, X-linked female restricted facial dysmorphism-short stature-choanal atresia-intellectual disability.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.87

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP9X	NM_001039591.3	c.911A>T	p.Asn304Ile	missense_variant	Exon 8 of 45	ENST00000378308.7	NP_001034680.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP9X	ENST00000378308.7	c.911A>T	p.Asn304Ile	missense_variant	Exon 8 of 45	5	NM_001039591.3	ENSP00000367558.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Oct 05, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	.;D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.1	D;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.81
MutPred		0.29		Loss of disorder (P = 0.0267);Loss of disorder (P = 0.0267);
MVP		0.82
MPC		1.4
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.90
gMVP		0.67

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: rs1555920902; hg19: chrX-41000359;