Genetic Variant NM_001039591.3:c.6084C>A (chrX-41216651-C-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_001039591.3(USP9X):c.6084C>A(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 0.00000184 in 1,087,316 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P2028P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000018 ( 0 hom. 0 hem. )

Consequence

USP9X
NM_001039591.3 splice_region, synonymous

Scores

Splicing: ADA: 0.00004593

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.51

Publications

0 publications found

Variant links:

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

USP9X links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP7

Synonymous conserved (PhyloP=3.51 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP9X	NM_001039591.3 link	c.6084C>A	p.Pro2028Pro	splice_region_variant, synonymous_variant	Exon 35 of 45	ENST00000378308.7	NP_001034680.2	Q93008-1Q86X58Q6P468

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP9X	ENST00000378308.7 link	c.6084C>A	p.Pro2028Pro	splice_region_variant, synonymous_variant	Exon 35 of 45	5	NM_001039591.3	ENSP00000367558.2		Q93008-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000184

AC:

AN:

1087316

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

354064

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26163

American (AMR)

AF:

0.00

AC:

AN:

34405

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18909

East Asian (EAS)

AF:

0.00

AC:

AN:

30032

South Asian (SAS)

AF:

0.00

AC:

AN:

52305

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40018

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4074

European-Non Finnish (NFE)

AF:

0.00000239

AC:

AN:

835769

Other (OTH)

AF:

0.00

AC:

AN:

45641

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

0.60

(source)

DANN

Benign

0.79

PhyloP100

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000046

dbscSNV1_RF

Benign

0.066

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over