Variant 12-62389449-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001252078.2(USP15):c.1492A>C(p.Lys498Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

USP15
NM_001252078.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.06

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:

USP15 (HGNC:):

USP15 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.798

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP15	NM_001252078.2 linkuse as main transcript	c.1492A>C	p.Lys498Gln	missense_variant	12/22	ENST00000280377.10	NP_001239007.1	Q9Y4E8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
USP15	ENST00000280377.10 linkuse as main transcript	c.1492A>C	p.Lys498Gln	missense_variant	12/22	1	NM_001252078.2	ENSP00000280377.5	Q9Y4E8-1
USP15	ENST00000353364.7 linkuse as main transcript	c.1405A>C	p.Lys469Gln	missense_variant	11/21	1		ENSP00000258123.4	Q9Y4E8-2
USP15	ENST00000549268.1 linkuse as main transcript	n.850A>C		non_coding_transcript_exon_variant	5/7	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249434

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134734

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1459386

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725848

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000225

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 22, 2024

The c.1405A>C (p.K469Q) alteration is located in exon 11 (coding exon 11) of the USP15 gene. This alteration results from a A to C substitution at nucleotide position 1405, causing the lysine (K) at amino acid position 469 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Uncertain

0.027

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

.;T

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.96

D;D

M_CAP

Benign

0.026

MetaRNN

Pathogenic

0.80

D;D

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.3

.;M

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-2.5

N;N

REVEL

Benign

0.20

Sift

Uncertain

0.015

D;D

Sift4G

Uncertain

0.042

D;D

Polyphen

0.98

D;D

Vest4

0.73

MutPred

0.50

.;Loss of ubiquitination at K498 (P = 0.0362);

MVP

0.53

MPC

1.5

ClinPred

0.90

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.39

gMVP

0.79

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over