chr15-50494133-G-A

Variant names:

• chr15-50494133-G-A
• rs79646551
• NM_005154.5:c.2511G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_005154.5(USP8):​c.2511G>A​(p.Leu837Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0015 in 1,611,988 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00081 (14 hom.)
• Consequence: USP8 NM_005154.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.407
• Publications: 1 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]

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]

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 15-50494133-G-A is Benign according to our data. Variant chr15-50494133-G-A is described in ClinVar as Benign. ClinVar VariationId is 528044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.407 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00807 (1230/152336) while in subpopulation AFR AF = 0.0284 (1179/41580). AF 95% confidence interval is 0.027. There are 14 homozygotes in GnomAd4. There are 566 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP8	NM_005154.5	MANE Select	c.2511G>A	p.Leu837Leu	synonymous	Exon 16 of 20	NP_005145.3
	USP8	NM_001128610.3		c.2511G>A	p.Leu837Leu	synonymous	Exon 16 of 20	NP_001122082.1
	USP8	NM_001283049.2		c.2193G>A	p.Leu731Leu	synonymous	Exon 13 of 17	NP_001269978.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP8	ENST00000307179.9	TSL:1 MANE Select	c.2511G>A	p.Leu837Leu	synonymous	Exon 16 of 20	ENSP00000302239.4
	USP8	ENST00000396444.7	TSL:1	c.2511G>A	p.Leu837Leu	synonymous	Exon 16 of 20	ENSP00000379721.3
	USP8	ENST00000425032.7	TSL:2	c.2193G>A	p.Leu731Leu	synonymous	Exon 13 of 17	ENSP00000412682.3

Frequencies

GnomAD3 genomes AF: 0.00809 AC: 1232 AN: 152218 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0285

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00200 AC: 500 AN: 249954 AF XY: 0.00139

Gnomad AFR exome AF: 0.0285

Gnomad AMR exome AF: 0.000906

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000494

GnomAD4 exome AF: 0.000813 AC: 1186 AN: 1459652 Hom.: 14 Cov.: 31 AF XY: 0.000675 AC XY: 490 AN XY: 726106

African (AFR) AF: 0.0305 AC: 1017 AN: 33384

American (AMR) AF: 0.000946 AC: 42 AN: 44390

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26054

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39670

South Asian (SAS) AF: 0.0000349 AC: 3 AN: 85902

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.000408 AC: 2 AN: 4898

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1111722

Other (OTH) AF: 0.00173 AC: 104 AN: 60226

GnomAD4 genome AF: 0.00807 AC: 1230 AN: 152336 Hom.: 14 Cov.: 32 AF XY: 0.00760 AC XY: 566 AN XY: 74486

African (AFR) AF: 0.0284 AC: 1179 AN: 41580

American (AMR) AF: 0.00261 AC: 40 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68026

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

Alfa AF: 0.00353 Hom.: 5

Bravo AF: 0.00919

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia Benign:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	10
DANN	Benign	0.79
PhyloP100		0.41
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs79646551; hg19: chr15-50786330;