rs115970610

Variant names:

• chr15-50481710-G-A
• rs115970610
• NM_005154.5:c.1448G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005154.5(USP8):​c.1448G>A​(p.Arg483Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000807 in 1,611,678 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (4 hom.)
• Consequence: USP8 NM_005154.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.65
• Publications: 2 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004116982).
• BP6: Variant 15-50481710-G-A is Benign according to our data. Variant chr15-50481710-G-A is described in ClinVar as Benign. ClinVar VariationId is 458313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.000479 (699/1459634) while in subpopulation AFR AF = 0.0168 (558/33246). AF 95% confidence interval is 0.0156. There are 4 homozygotes in GnomAdExome4. There are 282 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP8	NM_005154.5	MANE Select	c.1448G>A	p.Arg483Gln	missense	Exon 11 of 20	NP_005145.3
	USP8	NM_001128610.3		c.1448G>A	p.Arg483Gln	missense	Exon 11 of 20	NP_001122082.1	P40818-1
	USP8	NM_001283049.2		c.1217G>A	p.Arg406Gln	missense	Exon 9 of 17	NP_001269978.1	P40818-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP8	ENST00000307179.9	TSL:1 MANE Select	c.1448G>A	p.Arg483Gln	missense	Exon 11 of 20	ENSP00000302239.4	P40818-1
	USP8	ENST00000396444.7	TSL:1	c.1448G>A	p.Arg483Gln	missense	Exon 11 of 20	ENSP00000379721.3	P40818-1
	USP8	ENST00000956759.1		c.1574G>A	p.Arg525Gln	missense	Exon 12 of 21	ENSP00000626818.1

Frequencies

GnomAD3 genomes AF: 0.00395 AC: 600 AN: 151926 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0137

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00103 AC: 254 AN: 246302 AF XY: 0.000779

Gnomad AFR exome AF: 0.0138

Gnomad AMR exome AF: 0.000499

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000903

Gnomad OTH exome AF: 0.000834

GnomAD4 exome AF: 0.000479 AC: 699 AN: 1459634 Hom.: 4 Cov.: 31 AF XY: 0.000388 AC XY: 282 AN XY: 725970

African (AFR) AF: 0.0168 AC: 558 AN: 33246

American (AMR) AF: 0.000519 AC: 23 AN: 44292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39640

South Asian (SAS) AF: 0.0000468 AC: 4 AN: 85464

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53358

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 0.0000513 AC: 57 AN: 1111500

Other (OTH) AF: 0.000896 AC: 54 AN: 60278

GnomAD4 genome AF: 0.00396 AC: 602 AN: 152044 Hom.: 5 Cov.: 32 AF XY: 0.00386 AC XY: 287 AN XY: 74322

African (AFR) AF: 0.0137 AC: 568 AN: 41446

American (AMR) AF: 0.00124 AC: 19 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68004

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00223 Hom.: 1

Bravo AF: 0.00448

ESP6500AA AF: 0.0132 AC: 58

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00139 AC: 169

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	not provided (1)
-	-	1	USP8-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.043	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.062
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		3.6
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.017
Sift	Benign	0.13	T
Sift4G	Benign	0.28	T
Polyphen		0.0060	B
Vest4		0.17
MVP		0.49
ClinPred		0.012	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.052
gMVP		0.070
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs115970610; hg19: chr15-50773907; COSMIC: COSV105881306; COSMIC: COSV105881306;