15-50449392-A-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_005154.5(USP8):c.250-8A>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000148 in 1,555,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: USP8 NM_005154.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00004570
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.654

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 15-50449392-A-C is Benign according to our data. Variant chr15-50449392-A-C is described in ClinVar as [Benign]. Clinvar id is 781991.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USP8	NM_005154.5	c.250-8A>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000307179.9
USP8	NM_001128610.3	c.250-8A>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
USP8	NM_001283049.2	c.105-9608A>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USP8	ENST00000307179.9	c.250-8A>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_005154.5	P1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000221 AC: 49 AN: 221770 Hom.: 0 AF XY: 0.000224 AC XY: 27 AN XY: 120642

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000745

Gnomad ASJ exome AF: 0.00417

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000955

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000146 AC: 205 AN: 1403396 Hom.: 0 Cov.: 27 AF XY: 0.000155 AC XY: 108 AN XY: 697312

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000107

Gnomad4 ASJ exome AF: 0.00573

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000351

Gnomad4 OTH exome AF: 0.000398

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74356

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000540 Hom.: 0

Bravo AF: 0.000215

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 08, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
Cadd	Benign	11
Dann	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000046
dbscSNV1_RF	Benign	0.052
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: rs199586071; hg19: chr15-50741589; COSMIC: COSV105881351; COSMIC: COSV105881351;