rs4775889

Variant names:

• chr15-50484443-A-G
• rs4775889
• NM_005154.5:c.1890+82A>G

Your query was ambiguous. Multiple possible variants found:

• chr15-50484443-A-G
• chr15-50484443-A-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.1890+82A>G 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 1,105,046 control chromosomes in the GnomAD database, including 17,463 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 (1984 hom., cov: 32)
  • Exomes 𝑓: 0.17 (15479 hom.)
• Consequence: USP8 NM_005154.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0190
• Publications: 7 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=-0.84).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.261 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.1890+82A>G		intron	N/A	NP_005145.3
	USP8	NM_001128610.3		c.1890+82A>G		intron	N/A	NP_001122082.1	P40818-1
	USP8	NM_001283049.2		c.1572+2378A>G		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.1890+82A>G		intron	N/A	ENSP00000302239.4	P40818-1
	USP8	ENST00000396444.7	TSL:1	c.1890+82A>G		intron	N/A	ENSP00000379721.3	P40818-1
	USP8	ENST00000956759.1		c.2016+82A>G		intron	N/A	ENSP00000626818.1

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21386 AN: 152150 Hom.: 1985 Cov.: 32

Gnomad AFR AF: 0.0621

Gnomad AMI AF: 0.112

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.279

Gnomad EAS AF: 0.00288

Gnomad SAS AF: 0.202

Gnomad FIN AF: 0.0798

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.167

Gnomad OTH AF: 0.183

GnomAD4 exome AF: 0.169 AC: 160913 AN: 952778 Hom.: 15479 AF XY: 0.170 AC XY: 83952 AN XY: 492508

African (AFR) AF: 0.0653 AC: 1343 AN: 20574

American (AMR) AF: 0.319 AC: 9747 AN: 30596

Ashkenazi Jewish (ASJ) AF: 0.279 AC: 6056 AN: 21688

East Asian (EAS) AF: 0.000596 AC: 21 AN: 35230

South Asian (SAS) AF: 0.211 AC: 14298 AN: 67734

European-Finnish (FIN) AF: 0.0900 AC: 4463 AN: 49562

Middle Eastern (MID) AF: 0.286 AC: 1115 AN: 3904

European-Non Finnish (NFE) AF: 0.171 AC: 116600 AN: 680918

Other (OTH) AF: 0.171 AC: 7270 AN: 42572

GnomAD4 genome AF: 0.140 AC: 21393 AN: 152268 Hom.: 1984 Cov.: 32 AF XY: 0.139 AC XY: 10338 AN XY: 74444

African (AFR) AF: 0.0622 AC: 2583 AN: 41540

American (AMR) AF: 0.268 AC: 4099 AN: 15286

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

East Asian (EAS) AF: 0.00289 AC: 15 AN: 5190

South Asian (SAS) AF: 0.202 AC: 976 AN: 4834

European-Finnish (FIN) AF: 0.0798 AC: 847 AN: 10616

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

European-Non Finnish (NFE) AF: 0.167 AC: 11341 AN: 68014

Other (OTH) AF: 0.181 AC: 382 AN: 2112

Alfa AF: 0.138 Hom.: 302

Bravo AF: 0.153

Asia WGS AF: 0.0950 AC: 328 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.97
DANN	Benign	0.36
PhyloP100		0.019
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: rs4775889; hg19: chr15-50776640;