12-62384284-A-G

Variant names:

• chr12-62384284-A-G
• rs2044846
• NM_001252078.2:c.1455A>G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_001252078.2(USP15):​c.1455A>G​(p.Pro485Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.611 in 1,605,158 control chromosomes in the GnomAD database, including 300,818 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.59 (26317 hom., cov: 25)
  • Exomes 𝑓: 0.61 (274501 hom.)
• Consequence: USP15 NM_001252078.2 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.273

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 12-62384284-A-G is Benign according to our data. Variant chr12-62384284-A-G is described in ClinVar as [Benign]. Clinvar id is 3060073.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=0.273 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.619 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP15	NM_001252078.2	c.1455A>G	p.Pro485Pro	synonymous_variant	Exon 11 of 22	ENST00000280377.10	NP_001239007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP15	ENST00000280377.10	c.1455A>G	p.Pro485Pro	synonymous_variant	Exon 11 of 22	1	NM_001252078.2	ENSP00000280377.5
USP15	ENST00000353364.7	c.1368A>G	p.Pro456Pro	synonymous_variant	Exon 10 of 21	1		ENSP00000258123.4
USP15	ENST00000549268.1	n.813A>G		non_coding_transcript_exon_variant	Exon 4 of 7	5

Frequencies

GnomAD3 genomes AF: 0.594 AC: 87854 AN: 147968 Hom.: 26311 Cov.: 25

Gnomad AFR AF: 0.534

Gnomad AMI AF: 0.570

Gnomad AMR AF: 0.577

Gnomad ASJ AF: 0.567

Gnomad EAS AF: 0.586

Gnomad SAS AF: 0.527

Gnomad FIN AF: 0.718

Gnomad MID AF: 0.577

Gnomad NFE AF: 0.624

Gnomad OTH AF: 0.576

GnomAD3 exomes AF: 0.604 AC: 149724 AN: 248070 Hom.: 45516 AF XY: 0.600 AC XY: 80553 AN XY: 134254

Gnomad AFR exome AF: 0.536

Gnomad AMR exome AF: 0.596

Gnomad ASJ exome AF: 0.562

Gnomad EAS exome AF: 0.607

Gnomad SAS exome AF: 0.524

Gnomad FIN exome AF: 0.712

Gnomad NFE exome AF: 0.620

Gnomad OTH exome AF: 0.604

GnomAD4 exome AF: 0.613 AC: 892510 AN: 1457116 Hom.: 274501 Cov.: 37 AF XY: 0.610 AC XY: 442302 AN XY: 724848

Gnomad4 AFR exome AF: 0.526

Gnomad4 AMR exome AF: 0.594

Gnomad4 ASJ exome AF: 0.566

Gnomad4 EAS exome AF: 0.597

Gnomad4 SAS exome AF: 0.526

Gnomad4 FIN exome AF: 0.708

Gnomad4 NFE exome AF: 0.621

Gnomad4 OTH exome AF: 0.595

GnomAD4 genome AF: 0.594 AC: 87874 AN: 148042 Hom.: 26317 Cov.: 25 AF XY: 0.595 AC XY: 42912 AN XY: 72066

Gnomad4 AFR AF: 0.534

Gnomad4 AMR AF: 0.577

Gnomad4 ASJ AF: 0.567

Gnomad4 EAS AF: 0.587

Gnomad4 SAS AF: 0.527

Gnomad4 FIN AF: 0.718

Gnomad4 NFE AF: 0.624

Gnomad4 OTH AF: 0.570

Alfa AF: 0.609 Hom.: 17052

Bravo AF: 0.584

Asia WGS AF: 0.525 AC: 1831 AN: 3478

EpiCase AF: 0.606

EpiControl AF: 0.606

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

USP15-related disorder Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as 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	-0.63
CADD	Benign	4.5
DANN	Benign	0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2044846; hg19: chr12-62778065;