15-50484328-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_005154.5(USP8):c.1857T>C(p.Phe619Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0387 in 1,611,854 control chromosomes in the GnomAD database, including 3,142 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.090 ( 1336 hom., cov: 32)

Exomes 𝑓: 0.033 ( 1806 hom. )

Consequence

USP8
NM_005154.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.15

Publications

10 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 15-50484328-T-C is Benign according to our data. Variant chr15-50484328-T-C is described in ClinVar as Benign. ClinVar VariationId is 458314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.14 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.243 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP8	NM_005154.5 link	c.1857T>C	p.Phe619Phe	synonymous_variant	Exon 12 of 20	ENST00000307179.9	NP_005145.3	P40818-1A0A024R5S4A8K8N5
USP8	NM_001128610.3 link	c.1857T>C	p.Phe619Phe	synonymous_variant	Exon 12 of 20		NP_001122082.1	P40818-1A0A024R5S4
USP8	NM_001283049.2 link	c.1572+2263T>C		intron_variant	Intron 9 of 16		NP_001269978.1	P40818-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP8	ENST00000307179.9 link	c.1857T>C	p.Phe619Phe	synonymous_variant	Exon 12 of 20	1	NM_005154.5	ENSP00000302239.4		P40818-1

Frequencies

GnomAD3 genomes

AF:

0.0898

AC:

13656

AN:

152056

Hom.:

1335

Cov.:

show subpopulations

Gnomad AFR

AF:

0.247

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0559

Gnomad ASJ

AF:

0.0300

Gnomad EAS

AF:

0.0189

Gnomad SAS

AF:

0.0313

Gnomad FIN

AF:

0.0124

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0285

Gnomad OTH

AF:

0.0704

GnomAD2 exomes

AF:

0.0419

AC:

10455

AN:

249694

AF XY:

0.0389

show subpopulations

Gnomad AFR exome

AF:

0.257

Gnomad AMR exome

AF:

0.0315

Gnomad ASJ exome

AF:

0.0338

Gnomad EAS exome

AF:

0.0171

Gnomad FIN exome

AF:

0.0104

Gnomad NFE exome

AF:

0.0291

Gnomad OTH exome

AF:

0.0334

GnomAD4 exome

AF:

0.0334

AC:

48714

AN:

1459680

Hom.:

1806

Cov.:

AF XY:

0.0330

AC XY:

23930

AN XY:

726182

show subpopulations

African (AFR)

AF:

0.255

AC:

8473

AN:

33204

American (AMR)

AF:

0.0340

AC:

1507

AN:

44384

Ashkenazi Jewish (ASJ)

AF:

0.0356

AC:

928

AN:

26088

East Asian (EAS)

AF:

0.0142

AC:

562

AN:

39554

South Asian (SAS)

AF:

0.0305

AC:

2623

AN:

85952

European-Finnish (FIN)

AF:

0.0103

AC:

551

AN:

53384

Middle Eastern (MID)

AF:

0.0407

AC:

234

AN:

5744

European-Non Finnish (NFE)

AF:

0.0280

AC:

31164

AN:

1111082

Other (OTH)

AF:

0.0443

AC:

2672

AN:

60288

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

2054

4108

6162

8216

10270

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1292

2584

3876

5168

6460

<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

AF:

0.0899

AC:

13675

AN:

152174

Hom.:

1336

Cov.:

AF XY:

0.0876

AC XY:

6521

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.247

AC:

10242

AN:

41476

American (AMR)

AF:

0.0558

AC:

853

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0300

AC:

104

AN:

3470

East Asian (EAS)

AF:

0.0183

AC:

AN:

5184

South Asian (SAS)

AF:

0.0311

AC:

150

AN:

4826

European-Finnish (FIN)

AF:

0.0124

AC:

131

AN:

10604

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0285

AC:

1936

AN:

68008

Other (OTH)

AF:

0.0697

AC:

147

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

566

1133

1699

2266

2832

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

272

408

544

680

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0535

Hom.:

549

Bravo

AF:

0.100

Asia WGS

AF:

0.0420

AC:

147

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia

Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

8.3

(source)

DANN

Benign

0.71

PhyloP100

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over