15-50439193-C-T

Variant names:

• chr15-50439193-C-T
• rs11632708
• NM_005154.5:c.104+16C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005154.5(USP8):​c.104+16C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.165 in 1,365,970 control chromosomes in the GnomAD database, including 20,660 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2121 hom., cov: 32)
  • Exomes 𝑓: 0.17 (18539 hom.)
• Consequence: USP8 NM_005154.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0130
• 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 (BayesDel_noAF=-0.77).
• BP6: Variant 15-50439193-C-T is Benign according to our data. Variant chr15-50439193-C-T is described in ClinVar as Benign. ClinVar VariationId is 1600612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.265 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.104+16C>T		intron	N/A	NP_005145.3
	USP8	NM_001128610.3		c.104+16C>T		intron	N/A	NP_001122082.1	P40818-1
	USP8	NM_001283049.2		c.104+16C>T		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.104+16C>T		intron	N/A	ENSP00000302239.4	P40818-1
	USP8	ENST00000396444.7	TSL:1	c.104+16C>T		intron	N/A	ENSP00000379721.3	P40818-1
	USP8	ENST00000559329.5	TSL:1	n.104+16C>T		intron	N/A	ENSP00000454003.1	A0A075B720

Frequencies

GnomAD3 genomes AF: 0.151 AC: 22885 AN: 151988 Hom.: 2117 Cov.: 32

Gnomad AFR AF: 0.0973

Gnomad AMI AF: 0.112

Gnomad AMR AF: 0.272

Gnomad ASJ AF: 0.278

Gnomad EAS AF: 0.00288

Gnomad SAS AF: 0.201

Gnomad FIN AF: 0.0799

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.167

Gnomad OTH AF: 0.188

GnomAD2 exomes AF: 0.171 AC: 26317 AN: 154088 AF XY: 0.175

Gnomad AFR exome AF: 0.0954

Gnomad AMR exome AF: 0.344

Gnomad ASJ exome AF: 0.277

Gnomad EAS exome AF: 0.00235

Gnomad FIN exome AF: 0.0860

Gnomad NFE exome AF: 0.175

Gnomad OTH exome AF: 0.177

GnomAD4 exome AF: 0.167 AC: 203041 AN: 1213864 Hom.: 18539 Cov.: 17 AF XY: 0.169 AC XY: 101019 AN XY: 598878

African (AFR) AF: 0.0958 AC: 2373 AN: 24764

American (AMR) AF: 0.314 AC: 6999 AN: 22314

Ashkenazi Jewish (ASJ) AF: 0.276 AC: 5318 AN: 19248

East Asian (EAS) AF: 0.000934 AC: 30 AN: 32136

South Asian (SAS) AF: 0.208 AC: 11897 AN: 57306

European-Finnish (FIN) AF: 0.0890 AC: 4186 AN: 47036

Middle Eastern (MID) AF: 0.285 AC: 1407 AN: 4938

European-Non Finnish (NFE) AF: 0.170 AC: 162481 AN: 956542

Other (OTH) AF: 0.168 AC: 8350 AN: 49580

GnomAD4 genome AF: 0.151 AC: 22901 AN: 152106 Hom.: 2121 Cov.: 32 AF XY: 0.149 AC XY: 11063 AN XY: 74364

African (AFR) AF: 0.0975 AC: 4049 AN: 41532

American (AMR) AF: 0.272 AC: 4146 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 964 AN: 3468

East Asian (EAS) AF: 0.00289 AC: 15 AN: 5188

South Asian (SAS) AF: 0.201 AC: 970 AN: 4816

European-Finnish (FIN) AF: 0.0799 AC: 845 AN: 10576

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.167 AC: 11337 AN: 67956

Other (OTH) AF: 0.186 AC: 392 AN: 2112

Alfa AF: 0.179 Hom.: 3403

Bravo AF: 0.164

Asia WGS AF: 0.0990 AC: 344 AN: 3474

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
BayesDel_noAF	Benign	-0.77
CADD	Benign	14
DANN	Benign	0.82
PhyloP100		-0.013
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs11632708; hg19: chr15-50731390;