chr12-62390958-A-T

Position:

• chr12-62390958-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001252078.2(USP15):​c.1939A>T​(p.Ile647Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: USP15 NM_001252078.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.54

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07064873).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP15	NM_001252078.2	c.1939A>T	p.Ile647Leu	missense_variant	15/22	ENST00000280377.10	NP_001239007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP15	ENST00000280377.10	c.1939A>T	p.Ile647Leu	missense_variant	15/22	1	NM_001252078.2	ENSP00000280377	P3
USP15	ENST00000353364.7	c.1852A>T	p.Ile618Leu	missense_variant	14/21	1		ENSP00000258123	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 09, 2022

The c.1852A>T (p.I618L) alteration is located in exon 14 (coding exon 14) of the USP15 gene. This alteration results from a A to T substitution at nucleotide position 1852, causing the isoleucine (I) at amino acid position 618 to be replaced by a leucine (L). 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	Benign	0.075
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	16
DANN	Benign	0.90
DEOGEN2	Benign	0.053	.;T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.071	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.65	.;N
MutationTaster	Benign	0.69	D;D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.44	N;N
REVEL	Benign	0.042
Sift	Benign	0.90	T;T
Sift4G	Benign	0.83	T;T
Polyphen		0.0	B;B
Vest4		0.16
MutPred		0.33		.;Gain of catalytic residue at I647 (P = 0.0135);
MVP		0.15
MPC		0.61
ClinPred		0.20	T
GERP RS		3.4
Varity_R		0.049
gMVP		0.099

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-62784738;