Genetic Variant USP15:p.Thr457Thr (chr12-62384200-A-G) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

The NM_001252078.2(USP15):c.1371A>G(p.Thr457Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000316 in 1,613,090 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.0014 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 1 hom. )

Consequence

USP15
NM_001252078.2 synonymous

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.464

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 made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 12-62384200-A-G is Benign according to our data. Variant chr12-62384200-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3033240.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=0.464 with no splicing effect.

BS2

High AC in GnomAd4 at 209 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP15	NM_001252078.2 link	c.1371A>G	p.Thr457Thr	synonymous_variant	Exon 11 of 22	ENST00000280377.10	NP_001239007.1	Q9Y4E8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
USP15	ENST00000280377.10 link	c.1371A>G	p.Thr457Thr	synonymous_variant	Exon 11 of 22	1	NM_001252078.2	ENSP00000280377.5	Q9Y4E8-1
USP15	ENST00000353364.7 link	c.1284A>G	p.Thr428Thr	synonymous_variant	Exon 10 of 21	1		ENSP00000258123.4	Q9Y4E8-2
USP15	ENST00000549268.1 link	n.729A>G		non_coding_transcript_exon_variant	Exon 4 of 7	5

Frequencies

GnomAD3 genomes

AF:

0.00136

AC:

206

AN:

151804

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00452

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000987

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.000415

AC:

104

AN:

250874

Hom.:

AF XY:

0.000280

AC XY:

AN XY:

135610

show subpopulations

Gnomad AFR exome

AF:

0.00487

Gnomad AMR exome

AF:

0.000348

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:

0.0000705

Gnomad OTH exome

AF:

0.000654

GnomAD4 exome

AF:

0.000206

AC:

301

AN:

1461168

Hom.:

Cov.:

AF XY:

0.000162

AC XY:

118

AN XY:

726846

show subpopulations

Gnomad4 AFR exome

AF:

0.00574

Gnomad4 AMR exome

AF:

0.000582

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000396

Gnomad4 OTH exome

AF:

0.000580

GnomAD4 genome

AF:

0.00138

AC:

209

AN:

151922

Hom.:

Cov.:

AF XY:

0.00147

AC XY:

109

AN XY:

74286

show subpopulations

Gnomad4 AFR

AF:

0.00458

Gnomad4 AMR

AF:

0.000985

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.000816

Hom.:

Bravo

AF:

0.00195

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

USP15-related disorder

Benign:1

Jun 18, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

7.5

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

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