Genetic Variant USP8:p.Gln165Arg (chr15-50459158-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005154.5(USP8):c.494A>G(p.Gln165Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,448,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q165L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

USP8
NM_005154.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.91

Publications

0 publications found

Variant links:

Genes affected

USP8 (HGNC:12631): (ubiquitin specific peptidase 8) This gene encodes a protein that belongs to the ubiquitin-specific processing protease family of proteins. The encoded protein is thought to regulate the morphology of the endosome by ubiquitination of proteins on this organelle and is involved in cargo sorting and membrane trafficking at the early endosome stage. This protein is required for the cell to enter the S phase of the cell cycle and also functions as a positive regulator in the Hedgehog signaling pathway in development. Pseudogenes of this gene are present on chromosomes 2 and 6. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

USP8 Gene-Disease associations (from GenCC):

autosomal recessive spastic paraplegia type 59
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
complex neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
hereditary spastic paraplegia
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

USP8 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08702353).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005154.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
USP8	NM_005154.5	MANE Select	c.494A>G	p.Gln165Arg	missense	Exon 5 of 20	NP_005145.3
USP8	NM_001128610.3		c.494A>G	p.Gln165Arg	missense	Exon 5 of 20	NP_001122082.1	P40818-1
USP8	NM_001283049.2		c.263A>G	p.Gln88Arg	missense	Exon 3 of 17	NP_001269978.1	P40818-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
USP8	ENST00000307179.9	TSL:1 MANE Select	c.494A>G	p.Gln165Arg	missense	Exon 5 of 20	ENSP00000302239.4	P40818-1
USP8	ENST00000396444.7	TSL:1	c.494A>G	p.Gln165Arg	missense	Exon 5 of 20	ENSP00000379721.3	P40818-1
USP8	ENST00000559329.5	TSL:1	n.494A>G		non_coding_transcript_exon	Exon 6 of 12	ENSP00000454003.1	A0A075B720

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1448014

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

719710

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32486

American (AMR)

AF:

0.00

AC:

AN:

40686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25488

East Asian (EAS)

AF:

0.00

AC:

AN:

39604

South Asian (SAS)

AF:

0.00

AC:

AN:

82714

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53288

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

9.02e-7

AC:

AN:

1108230

Other (OTH)

AF:

0.00

AC:

AN:

59820

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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.060

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.25

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.69

M_CAP

Benign

0.0032

MetaRNN

Benign

0.087

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.3

PhyloP100

1.9

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.28

REVEL

Benign

0.036

Sift

Benign

0.33

Sift4G

Benign

0.48

Polyphen

0.0010

Vest4

0.099

MutPred

0.14

Gain of MoRF binding (P = 0.0214)

MVP

0.43

ClinPred

0.16

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.066

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over