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GeneBe

15-50459064-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_ModerateBP6_ModerateBP7BS1BS2

The NM_005154.5(USP8):c.400C>T(p.Leu134=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00221 in 1,613,840 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.012 ( 27 hom., cov: 32)
Exomes 𝑓: 0.0012 ( 44 hom. )

Consequence

USP8
NM_005154.5 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.50
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.42).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 15-50459064-C-T is Benign according to our data. Variant chr15-50459064-C-T is described in ClinVar as [Benign]. Clinvar id is 704630.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=3.51 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0118 (1796/152134) while in subpopulation AFR AF= 0.0409 (1698/41518). AF 95% confidence interval is 0.0393. There are 27 homozygotes in gnomad4. There are 829 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 1798 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
USP8NM_005154.5 linkuse as main transcriptc.400C>T p.Leu134= synonymous_variant 5/20 ENST00000307179.9
USP8NM_001128610.3 linkuse as main transcriptc.400C>T p.Leu134= synonymous_variant 5/20
USP8NM_001283049.2 linkuse as main transcriptc.169C>T p.Leu57= synonymous_variant 3/17

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
USP8ENST00000307179.9 linkuse as main transcriptc.400C>T p.Leu134= synonymous_variant 5/201 NM_005154.5 P1P40818-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0118
AC:
1798
AN:
152018
Hom.:
28
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0410
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00512
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00669
GnomAD3 exomes
AF:
0.00316
AC:
794
AN:
251368
Hom.:
24
AF XY:
0.00225
AC XY:
306
AN XY:
135872
show subpopulations
Gnomad AFR exome
AF:
0.0445
Gnomad AMR exome
AF:
0.00165
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000880
Gnomad OTH exome
AF:
0.000489
GnomAD4 exome
AF:
0.00121
AC:
1769
AN:
1461706
Hom.:
44
Cov.:
30
AF XY:
0.00102
AC XY:
739
AN XY:
727168
show subpopulations
Gnomad4 AFR exome
AF:
0.0435
Gnomad4 AMR exome
AF:
0.00201
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000486
Gnomad4 OTH exome
AF:
0.00268
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0118
AC:
1796
AN:
152134
Hom.:
27
Cov.:
32
AF XY:
0.0112
AC XY:
829
AN XY:
74350
show subpopulations
Gnomad4 AFR
AF:
0.0409
Gnomad4 AMR
AF:
0.00511
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00662
Alfa
AF:
0.00522
Hom.:
8
Bravo
AF:
0.0132
Asia WGS
AF:
0.00260
AC:
9
AN:
3478
EpiCase
AF:
0.000109
EpiControl
AF:
0.000237

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hereditary spastic paraplegia Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeDec 07, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.42
Cadd
Benign
13
Dann
Benign
0.78

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs114541731; hg19: chr15-50751261; API