Genetic Variant NM_005154.5:c.2658+5_2658+8dupGAAA (chr15-50494282-T-TAAGA) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_ModerateBS2

The NM_005154.5(USP8):c.2658+5_2658+8dupGAAA variant causes a intron change. The variant allele was found at a frequency of 0.00259 in 1,592,458 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0026 ( 8 hom. )

Consequence

USP8
NM_005154.5 intron

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter U:1B:1

Conservation

PhyloP100: 5.79

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 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP6

Variant 15-50494282-T-TAAGA is Benign according to our data. Variant chr15-50494282-T-TAAGA is described in ClinVar as Likely_benign. ClinVar VariationId is 458315.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 8 AR,AD gene

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	Effect	Exon Rank	Protein	UniProt
USP8	NM_005154.5	MANE Select	c.2658+5_2658+8dupGAAA	intron	N/A	NP_005145.3
USP8	NM_001128610.3		c.2658+5_2658+8dupGAAA	intron	N/A	NP_001122082.1	P40818-1
USP8	NM_001283049.2		c.2340+5_2340+8dupGAAA	intron	N/A	NP_001269978.1	P40818-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
USP8	ENST00000307179.9	TSL:1 MANE Select	c.2658+2_2658+3insAAGA	splice_region intron	N/A	ENSP00000302239.4	P40818-1
USP8	ENST00000396444.7	TSL:1	c.2658+2_2658+3insAAGA	splice_region intron	N/A	ENSP00000379721.3	P40818-1
USP8	ENST00000956759.1		c.2784+2_2784+3insAAGA	splice_region intron	N/A	ENSP00000626818.1

Frequencies

GnomAD3 genomes

AF:

0.00279

AC:

424

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.00236

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00452

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00403

Gnomad OTH

AF:

0.00334

GnomAD2 exomes

AF:

0.00275

AC:

626

AN:

227292

AF XY:

0.00289

show subpopulations

Gnomad AFR exome

AF:

0.000127

Gnomad AMR exome

AF:

0.00216

Gnomad ASJ exome

AF:

0.00529

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00293

Gnomad NFE exome

AF:

0.00384

Gnomad OTH exome

AF:

0.00294

GnomAD4 exome

AF:

0.00257

AC:

3699

AN:

1440120

Hom.:

Cov.:

AF XY:

0.00259

AC XY:

1856

AN XY:

716126

show subpopulations

African (AFR)

AF:

0.000530

AC:

AN:

32090

American (AMR)

AF:

0.00209

AC:

AN:

38258

Ashkenazi Jewish (ASJ)

AF:

0.00538

AC:

133

AN:

24724

East Asian (EAS)

AF:

0.00

AC:

AN:

39580

South Asian (SAS)

AF:

0.00167

AC:

138

AN:

82410

European-Finnish (FIN)

AF:

0.00250

AC:

132

AN:

52792

Middle Eastern (MID)

AF:

0.00698

AC:

AN:

5154

European-Non Finnish (NFE)

AF:

0.00271

AC:

2993

AN:

1105712

Other (OTH)

AF:

0.00286

AC:

170

AN:

59400

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

171

342

513

684

855

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

200

300

400

500

<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:

0.00278

AC:

423

AN:

152338

Hom.:

Cov.:

AF XY:

0.00295

AC XY:

220

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.000361

AC:

AN:

41578

American (AMR)

AF:

0.00235

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00375

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00166

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00452

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00403

AC:

274

AN:

68032

Other (OTH)

AF:

0.00331

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

120

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00313

Hom.:

Bravo

AF:

0.00241

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary spastic paraplegia (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.8

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over