15-50484443-A-G

Position:

• chr15-50484443-A-G

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP8	NM_005154.5	c.1890+82A>G		intron_variant		ENST00000307179.9	NP_005145.3
USP8	NM_001128610.3	c.1890+82A>G		intron_variant			NP_001122082.1
USP8	NM_001283049.2	c.1572+2378A>G		intron_variant			NP_001269978.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP8	ENST00000307179.9	c.1890+82A>G		intron_variant		1	NM_005154.5	ENSP00000302239	P1
USP8	ENST00000396444.7	c.1890+82A>G		intron_variant		1		ENSP00000379721	P1
USP8	ENST00000425032.7	c.1572+2378A>G		intron_variant		2		ENSP00000412682

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

Gnomad4 AFR exome AF: 0.0653

Gnomad4 AMR exome AF: 0.319

Gnomad4 ASJ exome AF: 0.279

Gnomad4 EAS exome AF: 0.000596

Gnomad4 SAS exome AF: 0.211

Gnomad4 FIN exome AF: 0.0900

Gnomad4 NFE exome AF: 0.171

Gnomad4 OTH exome AF: 0.171

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

Gnomad4 AFR AF: 0.0622

Gnomad4 AMR AF: 0.268

Gnomad4 ASJ AF: 0.279

Gnomad4 EAS AF: 0.00289

Gnomad4 SAS AF: 0.202

Gnomad4 FIN AF: 0.0798

Gnomad4 NFE AF: 0.167

Gnomad4 OTH AF: 0.181

Alfa AF: 0.140 Hom.: 299

Bravo AF: 0.153

Asia WGS AF: 0.0950 AC: 328 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.97
DANN	Benign	0.36

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

Publications

LitVar

Other links and lift over

dbSNP: rs4775889; hg19: chr15-50776640;