chr15-50484328-T-C

Variant names:

• chr15-50484328-T-C
• rs10220843
• NM_005154.5:c.1857T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005154.5(USP8):​c.1857T>C​(p.Phe619Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0387 in 1,611,854 control chromosomes in the GnomAD database, including 3,142 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.090 (1336 hom., cov: 32)
  • Exomes 𝑓: 0.033 (1806 hom.)
• Consequence: USP8 NM_005154.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.15
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 15-50484328-T-C is Benign according to our data. Variant chr15-50484328-T-C is described in ClinVar as Benign. ClinVar VariationId is 458314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.14 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.243 is higher than 0.05.

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.1857T>C	p.Phe619Phe	synonymous	Exon 12 of 20	NP_005145.3
	USP8	NM_001128610.3		c.1857T>C	p.Phe619Phe	synonymous	Exon 12 of 20	NP_001122082.1	P40818-1
	USP8	NM_001283049.2		c.1572+2263T>C		intron	N/A	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.1857T>C	p.Phe619Phe	synonymous	Exon 12 of 20	ENSP00000302239.4	P40818-1
	USP8	ENST00000396444.7	TSL:1	c.1857T>C	p.Phe619Phe	synonymous	Exon 12 of 20	ENSP00000379721.3	P40818-1
	USP8	ENST00000956759.1		c.1983T>C	p.Phe661Phe	synonymous	Exon 13 of 21	ENSP00000626818.1

Frequencies

GnomAD3 genomes AF: 0.0898 AC: 13656 AN: 152056 Hom.: 1335 Cov.: 32

Gnomad AFR AF: 0.247

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0559

Gnomad ASJ AF: 0.0300

Gnomad EAS AF: 0.0189

Gnomad SAS AF: 0.0313

Gnomad FIN AF: 0.0124

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0285

Gnomad OTH AF: 0.0704

GnomAD2 exomes AF: 0.0419 AC: 10455 AN: 249694 AF XY: 0.0389

Gnomad AFR exome AF: 0.257

Gnomad AMR exome AF: 0.0315

Gnomad ASJ exome AF: 0.0338

Gnomad EAS exome AF: 0.0171

Gnomad FIN exome AF: 0.0104

Gnomad NFE exome AF: 0.0291

Gnomad OTH exome AF: 0.0334

GnomAD4 exome AF: 0.0334 AC: 48714 AN: 1459680 Hom.: 1806 Cov.: 30 AF XY: 0.0330 AC XY: 23930 AN XY: 726182

African (AFR) AF: 0.255 AC: 8473 AN: 33204

American (AMR) AF: 0.0340 AC: 1507 AN: 44384

Ashkenazi Jewish (ASJ) AF: 0.0356 AC: 928 AN: 26088

East Asian (EAS) AF: 0.0142 AC: 562 AN: 39554

South Asian (SAS) AF: 0.0305 AC: 2623 AN: 85952

European-Finnish (FIN) AF: 0.0103 AC: 551 AN: 53384

Middle Eastern (MID) AF: 0.0407 AC: 234 AN: 5744

European-Non Finnish (NFE) AF: 0.0280 AC: 31164 AN: 1111082

Other (OTH) AF: 0.0443 AC: 2672 AN: 60288

GnomAD4 genome AF: 0.0899 AC: 13675 AN: 152174 Hom.: 1336 Cov.: 32 AF XY: 0.0876 AC XY: 6521 AN XY: 74414

African (AFR) AF: 0.247 AC: 10242 AN: 41476

American (AMR) AF: 0.0558 AC: 853 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0300 AC: 104 AN: 3470

East Asian (EAS) AF: 0.0183 AC: 95 AN: 5184

South Asian (SAS) AF: 0.0311 AC: 150 AN: 4826

European-Finnish (FIN) AF: 0.0124 AC: 131 AN: 10604

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0285 AC: 1936 AN: 68008

Other (OTH) AF: 0.0697 AC: 147 AN: 2110

Alfa AF: 0.0535 Hom.: 549

Bravo AF: 0.100

Asia WGS AF: 0.0420 AC: 147 AN: 3478

ClinVar

ClinVar submissions as Germline

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
BayesDel_noAF	Benign	-0.57
CADD	Benign	8.3
DANN	Benign	0.71
PhyloP100		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs10220843; hg19: chr15-50776525; COSMIC: COSV56164513; COSMIC: COSV56164513;