rs61751062

Positions:

• chr15-50471748-T-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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, single submitter B:1
• Conservation: PhyloP100: 2.84

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]

ACMG classification

Verdict is Benign. Variant got -14 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 id is 458317.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-50471748-T-A is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2492 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USP8	NM_005154.5	c.802T>A	p.Leu268Ile	missense_variant	8/20	ENST00000307179.9
USP8	NM_001128610.3	c.802T>A	p.Leu268Ile	missense_variant	8/20
USP8	NM_001283049.2	c.571T>A	p.Leu191Ile	missense_variant	6/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USP8	ENST00000307179.9	c.802T>A	p.Leu268Ile	missense_variant	8/20	1	NM_005154.5	P1

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

GnomAD3 exomes AF: 0.0160 AC: 4011 AN: 251216 Hom.: 53 AF XY: 0.0167 AC XY: 2272 AN XY: 135774

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 SAS exome AF: 0.00840

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

Gnomad4 AFR exome AF: 0.00373

Gnomad4 AMR exome AF: 0.0138

Gnomad4 ASJ exome AF: 0.0238

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00929

Gnomad4 FIN exome AF: 0.00406

Gnomad4 NFE exome AF: 0.0251

Gnomad4 OTH exome AF: 0.0204

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

Gnomad4 AFR AF: 0.00505

Gnomad4 AMR AF: 0.0225

Gnomad4 ASJ AF: 0.0230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00935

Gnomad4 FIN AF: 0.00368

Gnomad4 NFE AF: 0.0252

Gnomad4 OTH AF: 0.0213

Alfa AF: 0.0224 Hom.: 24

Bravo AF: 0.0170

TwinsUK AF: 0.0251 AC: 93

ALSPAC AF: 0.0208 AC: 80

ESP6500AA AF: 0.00569 AC: 25

ESP6500EA AF: 0.0255 AC: 219

ExAC AF: 0.0156 AC: 1894

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0285

EpiControl AF: 0.0289

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

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;T;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.94	D
MetaRNN	Benign	0.0068	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.8	M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.56	N;N;N
REVEL	Benign	0.17
Sift	Benign	0.065	T;T;D
Sift4G	Benign	0.25	T;T;T
Polyphen		1.0	D;D;.
Vest4		0.35
ClinPred		0.025	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.34

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

Publications

LitVar

Other links and lift over

dbSNP: rs61751062; hg19: chr15-50763945; COSMIC: COSV99048054; COSMIC: COSV99048054;