rs61751062

Variant names:

• chr15-50471748-T-A
• rs61751062
• NM_005154.5:c.802T>A
• USP8 p.Leu268Ile

Your query was ambiguous. Multiple possible variants found:

• chr15-50471748-T-A
• chr15-50471748-T-G

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.802T>A​(p.Leu268Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0211 in 1,614,050 control chromosomes in the GnomAD database, including 433 homozygotes. In-silico tool predicts 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. L268V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.016 (25 hom., cov: 32)
  • Exomes 𝑓: 0.022 (408 hom.)
• Consequence: USP8 NM_005154.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.84
• Publications: 15 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=0.0067777038).
• BP6: Variant 15-50471748-T-A is Benign according to our data. Variant chr15-50471748-T-A is described in ClinVar as Benign. ClinVar VariationId is 458317.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 = 0.0164 (2492/152274) while in subpopulation NFE AF = 0.0252 (1717/68010). AF 95% confidence interval is 0.0243. There are 25 homozygotes in GnomAd4. There are 1154 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 25 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.802T>A	p.Leu268Ile	missense	Exon 8 of 20	NP_005145.3
	USP8	NM_001128610.3		c.802T>A	p.Leu268Ile	missense	Exon 8 of 20	NP_001122082.1	P40818-1
	USP8	NM_001283049.2		c.571T>A	p.Leu191Ile	missense	Exon 6 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.802T>A	p.Leu268Ile	missense	Exon 8 of 20	ENSP00000302239.4	P40818-1
	USP8	ENST00000396444.7	TSL:1	c.802T>A	p.Leu268Ile	missense	Exon 8 of 20	ENSP00000379721.3	P40818-1
	USP8	ENST00000559329.5	TSL:1	n.802T>A		non_coding_transcript_exon	Exon 9 of 12	ENSP00000454003.1	A0A075B720

Frequencies

GnomAD3 genomes AF: 0.0164 AC: 2491 AN: 152156 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.00507

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0225

Gnomad ASJ AF: 0.0230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00913

Gnomad FIN AF: 0.00368

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0253

Gnomad OTH AF: 0.0210

GnomAD2 exomes AF: 0.0160 AC: 4011 AN: 251216 AF XY: 0.0167

Gnomad AFR exome AF: 0.00418

Gnomad AMR exome AF: 0.0134

Gnomad ASJ exome AF: 0.0227

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00296

Gnomad NFE exome AF: 0.0248

Gnomad OTH exome AF: 0.0173

GnomAD4 exome AF: 0.0216 AC: 31566 AN: 1461776 Hom.: 408 Cov.: 31 AF XY: 0.0212 AC XY: 15406 AN XY: 727190

African (AFR) AF: 0.00373 AC: 125 AN: 33478

American (AMR) AF: 0.0138 AC: 619 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0238 AC: 622 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00929 AC: 801 AN: 86248

European-Finnish (FIN) AF: 0.00406 AC: 217 AN: 53416

Middle Eastern (MID) AF: 0.0146 AC: 84 AN: 5768

European-Non Finnish (NFE) AF: 0.0251 AC: 27866 AN: 1111958

Other (OTH) AF: 0.0204 AC: 1232 AN: 60392

GnomAD4 genome AF: 0.0164 AC: 2492 AN: 152274 Hom.: 25 Cov.: 32 AF XY: 0.0155 AC XY: 1154 AN XY: 74466

African (AFR) AF: 0.00505 AC: 210 AN: 41570

American (AMR) AF: 0.0225 AC: 344 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0230 AC: 80 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00935 AC: 45 AN: 4814

European-Finnish (FIN) AF: 0.00368 AC: 39 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0252 AC: 1717 AN: 68010

Other (OTH) AF: 0.0213 AC: 45 AN: 2116

Alfa AF: 0.0224 Hom.: 24

Bravo AF: 0.0170

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0285

EpiControl AF: 0.0289

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	0.11
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.8
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.17
Sift	Benign	0.065	T
Sift4G	Benign	0.25	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.34
Mutation Taster		=80/20	polymorphism (auto)

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

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

Other links and lift over

dbSNP: rs61751062;

hg19: chr15-50763945;

COSMIC: COSV99048054;

COSMIC: COSV99048054;