rs61733869

Variant names:

• chr15-50477323-G-A
• rs61733869
• NM_005154.5:c.1042G>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.1042G>A​(p.Ala348Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0372 in 1,613,798 control chromosomes in the GnomAD database, including 1,332 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A348S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.026 (78 hom., cov: 32)
  • Exomes 𝑓: 0.038 (1254 hom.)
• Consequence: USP8 NM_005154.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.114
• Publications: 10 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=0.001880914).
• BP6: Variant 15-50477323-G-A is Benign according to our data. Variant chr15-50477323-G-A is described in ClinVar as Benign. ClinVar VariationId is 458310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.026 (3952/152178) while in subpopulation NFE AF = 0.0416 (2827/68000). AF 95% confidence interval is 0.0403. There are 78 homozygotes in GnomAd4. There are 1787 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 78 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.1042G>A	p.Ala348Thr	missense	Exon 10 of 20	NP_005145.3
	USP8	NM_001128610.3		c.1042G>A	p.Ala348Thr	missense	Exon 10 of 20	NP_001122082.1	P40818-1
	USP8	NM_001283049.2		c.811G>A	p.Ala271Thr	missense	Exon 8 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.1042G>A	p.Ala348Thr	missense	Exon 10 of 20	ENSP00000302239.4	P40818-1
	USP8	ENST00000396444.7	TSL:1	c.1042G>A	p.Ala348Thr	missense	Exon 10 of 20	ENSP00000379721.3	P40818-1
	USP8	ENST00000559329.5	TSL:1	n.1042G>A		non_coding_transcript_exon	Exon 11 of 12	ENSP00000454003.1	A0A075B720

Frequencies

GnomAD3 genomes AF: 0.0260 AC: 3954 AN: 152060 Hom.: 78 Cov.: 32

Gnomad AFR AF: 0.00833

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0273

Gnomad ASJ AF: 0.0343

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.0133

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0416

Gnomad OTH AF: 0.0316

GnomAD2 exomes AF: 0.0259 AC: 6498 AN: 250846 AF XY: 0.0266

Gnomad AFR exome AF: 0.00650

Gnomad AMR exome AF: 0.0177

Gnomad ASJ exome AF: 0.0310

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0166

Gnomad NFE exome AF: 0.0414

Gnomad OTH exome AF: 0.0319

GnomAD4 exome AF: 0.0384 AC: 56111 AN: 1461620 Hom.: 1254 Cov.: 31 AF XY: 0.0375 AC XY: 27287 AN XY: 727122

African (AFR) AF: 0.00681 AC: 228 AN: 33478

American (AMR) AF: 0.0194 AC: 868 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0306 AC: 799 AN: 26128

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39682

South Asian (SAS) AF: 0.00707 AC: 610 AN: 86242

European-Finnish (FIN) AF: 0.0187 AC: 1000 AN: 53412

Middle Eastern (MID) AF: 0.00919 AC: 53 AN: 5768

European-Non Finnish (NFE) AF: 0.0454 AC: 50441 AN: 1111816

Other (OTH) AF: 0.0349 AC: 2110 AN: 60384

GnomAD4 genome AF: 0.0260 AC: 3952 AN: 152178 Hom.: 78 Cov.: 32 AF XY: 0.0240 AC XY: 1787 AN XY: 74398

African (AFR) AF: 0.00831 AC: 345 AN: 41536

American (AMR) AF: 0.0272 AC: 416 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0343 AC: 119 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00622 AC: 30 AN: 4822

European-Finnish (FIN) AF: 0.0133 AC: 141 AN: 10578

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0416 AC: 2827 AN: 68000

Other (OTH) AF: 0.0313 AC: 66 AN: 2112

Alfa AF: 0.0372 Hom.: 292

Bravo AF: 0.0270

TwinsUK AF: 0.0372 AC: 138

ALSPAC AF: 0.0410 AC: 158

ESP6500AA AF: 0.0105 AC: 46

ESP6500EA AF: 0.0434 AC: 373

ExAC AF: 0.0255 AC: 3090

Asia WGS AF: 0.00462 AC: 17 AN: 3476

EpiCase AF: 0.0426

EpiControl AF: 0.0424

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.54
DANN	Benign	0.37
DEOGEN2	Benign	0.025	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N
PhyloP100		-0.11
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.26	N
REVEL	Benign	0.050
Sift	Benign	0.52	T
Sift4G	Benign	0.59	T
Polyphen		0.0	B
Vest4		0.020
ClinPred		0.0012	T
GERP RS		-9.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.017
gMVP		0.17
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs61733869; hg19: chr15-50769520;