Genetic Variant USP15:p.Gln285Lys (chr12-62355413-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001252078.2(USP15):c.853C>A(p.Gln285Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q285E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

USP15
NM_001252078.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.29

Publications

0 publications found

Variant links:

Genes affected

USP15 (HGNC:12613): (ubiquitin specific peptidase 15) This gene encodes a member of the ubiquitin specific protease (USP) family of deubiquitinating enzymes. USP enzymes play critical roles in ubiquitin-dependent processes through polyubiquitin chain disassembly and hydrolysis of ubiquitin-substrate bonds. The encoded protein associates with the COP9 signalosome, and also plays a role in transforming growth factor beta signalling through deubiquitination of receptor-activated SMAD transcription factors. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 2. [provided by RefSeq, Nov 2011]

USP15 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2804636).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001252078.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
USP15	NM_001252078.2	MANE Select	c.853C>A	p.Gln285Lys	missense	Exon 8 of 22	NP_001239007.1	Q9Y4E8-1
USP15	NM_006313.3		c.766C>A	p.Gln256Lys	missense	Exon 7 of 21	NP_006304.1	Q9Y4E8-2
USP15	NM_001351159.2		c.490C>A	p.Gln164Lys	missense	Exon 9 of 23	NP_001338088.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
USP15	ENST00000280377.10	TSL:1 MANE Select	c.853C>A	p.Gln285Lys	missense	Exon 8 of 22	ENSP00000280377.5	Q9Y4E8-1
USP15	ENST00000353364.7	TSL:1	c.766C>A	p.Gln256Lys	missense	Exon 7 of 21	ENSP00000258123.4	Q9Y4E8-2
USP15	ENST00000957648.1		c.976C>A	p.Gln326Lys	missense	Exon 9 of 23	ENSP00000627707.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459078

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725806

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33386

American (AMR)

AF:

0.00

AC:

AN:

44558

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26014

East Asian (EAS)

AF:

0.00

AC:

AN:

39572

South Asian (SAS)

AF:

0.0000116

AC:

AN:

85938

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53286

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110338

Other (OTH)

AF:

0.00

AC:

AN:

60236

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.098

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.0084

MetaRNN

Benign

0.28

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

PhyloP100

5.3

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.15

Sift

Benign

0.073

Sift4G

Benign

0.49

Polyphen

0.58

Vest4

0.29

MutPred

0.32

Gain of ubiquitination at Q285 (P = 0.0054)

MVP

0.49

MPC

1.3

ClinPred

0.66

GERP RS

5.4

Varity_R

0.30

gMVP

0.39

Mutation Taster

=67/33

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over