rs4775886

Variant names:

• chr15-50430415-C-T
• rs4775886
• NM_005154.5:c.-66+5901C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005154.5(USP8):​c.-66+5901C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 151,878 control chromosomes in the GnomAD database, including 1,963 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.14 (1963 hom., cov: 31)
• Consequence: USP8 NM_005154.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.661
• Publications: 6 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.261 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP8	NM_005154.5	c.-66+5901C>T		intron_variant	Intron 1 of 19	ENST00000307179.9	NP_005145.3
USP8	NM_001128610.3	c.-66+5761C>T		intron_variant	Intron 1 of 19		NP_001122082.1
USP8	NM_001283049.2	c.-66+5901C>T		intron_variant	Intron 1 of 16		NP_001269978.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP8	ENST00000307179.9	c.-66+5901C>T		intron_variant	Intron 1 of 19	1	NM_005154.5	ENSP00000302239.4

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21141 AN: 151760 Hom.: 1964 Cov.: 31

Gnomad AFR AF: 0.0583

Gnomad AMI AF: 0.112

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.279

Gnomad EAS AF: 0.00271

Gnomad SAS AF: 0.201

Gnomad FIN AF: 0.0792

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.182

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.139 AC: 21143 AN: 151878 Hom.: 1963 Cov.: 31 AF XY: 0.138 AC XY: 10221 AN XY: 74224

African (AFR) AF: 0.0583 AC: 2414 AN: 41442

American (AMR) AF: 0.268 AC: 4071 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.279 AC: 967 AN: 3470

East Asian (EAS) AF: 0.00272 AC: 14 AN: 5154

South Asian (SAS) AF: 0.202 AC: 970 AN: 4810

European-Finnish (FIN) AF: 0.0792 AC: 835 AN: 10542

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

European-Non Finnish (NFE) AF: 0.166 AC: 11310 AN: 67940

Other (OTH) AF: 0.180 AC: 379 AN: 2104

Alfa AF: 0.148 Hom.: 356

Bravo AF: 0.151

Asia WGS AF: 0.0930 AC: 323 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.4
DANN	Benign	0.41
PhyloP100		-0.66
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs4775886; hg19: chr15-50722612;