rs371064052

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_005154.5(USP8):c.2320C>G(p.Pro774Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000186 in 1,613,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

USP8
NM_005154.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.25

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 links:

USP50 (HGNC:20079): (ubiquitin specific peptidase 50) Enables ubiquitin-like protein-specific protease activity. Acts upstream of or within several processes, including nuclear speck organization; positive regulation of NLRP3 inflammasome complex assembly; and positive regulation of macromolecule metabolic process. Predicted to be active in several cellular components, including dendritic spine; midbody; and postsynaptic density. Predicted to be extrinsic component of endosome membrane and extrinsic component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

USP50 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2961412).

BS2

High AC in GnomAdExome4 at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP8	NM_005154.5 link	c.2320C>G	p.Pro774Ala	missense_variant	Exon 15 of 20	ENST00000307179.9	NP_005145.3	P40818-1A0A024R5S4A8K8N5
USP8	NM_001128610.3 link	c.2320C>G	p.Pro774Ala	missense_variant	Exon 15 of 20		NP_001122082.1	P40818-1A0A024R5S4
USP8	NM_001283049.2 link	c.2002C>G	p.Pro668Ala	missense_variant	Exon 12 of 17		NP_001269978.1	P40818-2
USP50	XR_007064444.1 link	n.*239G>C		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
USP8	ENST00000307179.9 link	c.2320C>G	p.Pro774Ala	missense_variant	Exon 15 of 20	1	NM_005154.5	ENSP00000302239.4	P40818-1
USP8	ENST00000396444.7 link	c.2320C>G	p.Pro774Ala	missense_variant	Exon 15 of 20	1		ENSP00000379721.3	P40818-1
USP8	ENST00000425032.7 link	c.2002C>G	p.Pro668Ala	missense_variant	Exon 12 of 17	2		ENSP00000412682.3	P40818-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251314

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135824

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000198

AC:

AN:

1461854

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000261

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia

Uncertain:1

Jul 26, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 577918). This variant has not been reported in the literature in individuals affected with USP8-related conditions. This variant is present in population databases (rs371064052, gnomAD 0.004%). This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 774 of the USP8 protein (p.Pro774Ala). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.089

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.79

DEOGEN2

Benign

0.40

T;T;.

Eigen

Benign

-0.025

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.93

.;D;D

M_CAP

Benign

0.0086

MetaRNN

Benign

0.30

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

L;L;.

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-2.4

N;N;N

REVEL

Benign

0.16

Sift

Benign

0.37

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.25

B;B;.

Vest4

0.57

MVP

0.23

ClinPred

0.26

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.19

gMVP

0.35

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over