15-50439016-G-C

Position:

• chr15-50439016-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005154.5(USP8):​c.-58G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 1,193,454 control chromosomes in the GnomAD database, including 19,046 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2045 hom., cov: 32)
  • Exomes 𝑓: 0.17 (17001 hom.)
• Consequence: USP8 NM_005154.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.360

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 15-50439016-G-C is Benign according to our data. Variant chr15-50439016-G-C is described in ClinVar as [Benign]. Clinvar id is 1295795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.264 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP8	NM_005154.5	c.-58G>C		5_prime_UTR_variant	2/20	ENST00000307179.9	NP_005145.3
USP8	NM_001128610.3	c.-58G>C		5_prime_UTR_variant	2/20		NP_001122082.1
USP8	NM_001283049.2	c.-58G>C		5_prime_UTR_variant	2/17		NP_001269978.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP8	ENST00000307179.9	c.-58G>C		5_prime_UTR_variant	2/20	1	NM_005154.5	ENSP00000302239	P1

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22087 AN: 151908 Hom.: 2042 Cov.: 32

Gnomad AFR AF: 0.0791

Gnomad AMI AF: 0.112

Gnomad AMR AF: 0.271

Gnomad ASJ AF: 0.279

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.201

Gnomad FIN AF: 0.0794

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.167

Gnomad OTH AF: 0.185

GnomAD4 exome AF: 0.170 AC: 176971 AN: 1041428 Hom.: 17001 Cov.: 13 AF XY: 0.171 AC XY: 91642 AN XY: 534516

Gnomad4 AFR exome AF: 0.0772

Gnomad4 AMR exome AF: 0.318

Gnomad4 ASJ exome AF: 0.278

Gnomad4 EAS exome AF: 0.000665

Gnomad4 SAS exome AF: 0.210

Gnomad4 FIN exome AF: 0.0892

Gnomad4 NFE exome AF: 0.172

Gnomad4 OTH exome AF: 0.170

GnomAD4 genome AF: 0.145 AC: 22099 AN: 152026 Hom.: 2045 Cov.: 32 AF XY: 0.143 AC XY: 10652 AN XY: 74326

Gnomad4 AFR AF: 0.0793

Gnomad4 AMR AF: 0.271

Gnomad4 ASJ AF: 0.279

Gnomad4 EAS AF: 0.00289

Gnomad4 SAS AF: 0.201

Gnomad4 FIN AF: 0.0794

Gnomad4 NFE AF: 0.167

Gnomad4 OTH AF: 0.183

Alfa AF: 0.136 Hom.: 212

Bravo AF: 0.158

Asia WGS AF: 0.0980 AC: 338 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.0
DANN	Benign	0.71

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: rs11632697; hg19: chr15-50731213;