NM_005154.5:c.-66+357G>A

Variant names:

• chr15-50424871-G-A
• rs7174015
• NM_005154.5:c.-66+357G>A

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+357G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.475 in 149,826 control chromosomes in the GnomAD database, including 17,270 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 0.47 (17270 hom., cov: 28)
• Consequence: USP8 NM_005154.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0460
• Publications: 11 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=-0.78).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.565 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP8	NM_005154.5	c.-66+357G>A		intron_variant	Intron 1 of 19	ENST00000307179.9	NP_005145.3
USP8	NM_001128610.3	c.-66+217G>A		intron_variant	Intron 1 of 19		NP_001122082.1
USP8	NM_001283049.2	c.-66+357G>A		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+357G>A		intron_variant	Intron 1 of 19	1	NM_005154.5	ENSP00000302239.4

Frequencies

GnomAD3 genomes AF: 0.475 AC: 71045 AN: 149712 Hom.: 17266 Cov.: 28

Gnomad AFR AF: 0.569

Gnomad AMI AF: 0.492

Gnomad AMR AF: 0.548

Gnomad ASJ AF: 0.488

Gnomad EAS AF: 0.583

Gnomad SAS AF: 0.490

Gnomad FIN AF: 0.326

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.412

Gnomad OTH AF: 0.493

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

GnomAD4 genome AF: 0.475 AC: 71098 AN: 149826 Hom.: 17270 Cov.: 28 AF XY: 0.477 AC XY: 34752 AN XY: 72916

African (AFR) AF: 0.569 AC: 23199 AN: 40746

American (AMR) AF: 0.548 AC: 8261 AN: 15084

Ashkenazi Jewish (ASJ) AF: 0.488 AC: 1686 AN: 3454

East Asian (EAS) AF: 0.583 AC: 2973 AN: 5102

South Asian (SAS) AF: 0.489 AC: 2326 AN: 4758

European-Finnish (FIN) AF: 0.326 AC: 3203 AN: 9830

Middle Eastern (MID) AF: 0.524 AC: 154 AN: 294

European-Non Finnish (NFE) AF: 0.412 AC: 27821 AN: 67560

Other (OTH) AF: 0.492 AC: 1027 AN: 2088

Alfa AF: 0.426 Hom.: 3958

Bravo AF: 0.494

Asia WGS AF: 0.524 AC: 1818 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.9
DANN	Benign	0.73
PhyloP100		-0.046
PromoterAI		-0.062	Neutral
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: rs7174015; hg19: chr15-50717068;