12-62314887-C-T

Variant names:

• chr12-62314887-C-T
• rs753767001
• NM_001252078.2:c.446C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001252078.2(USP15):​c.446C>T​(p.Thr149Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000754 in 1,591,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: USP15 NM_001252078.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.28
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.38069034).
• BS2: High AC in GnomAd4 at 8 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP15	NM_001252078.2	MANE Select	c.446C>T	p.Thr149Ile	missense	Exon 4 of 22	NP_001239007.1	Q9Y4E8-1
	USP15	NM_006313.3		c.446C>T	p.Thr149Ile	missense	Exon 4 of 21	NP_006304.1	Q9Y4E8-2
	USP15	NM_001351159.2		c.83C>T	p.Thr28Ile	missense	Exon 5 of 23	NP_001338088.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP15	ENST00000280377.10	TSL:1 MANE Select	c.446C>T	p.Thr149Ile	missense	Exon 4 of 22	ENSP00000280377.5	Q9Y4E8-1
	USP15	ENST00000353364.7	TSL:1	c.446C>T	p.Thr149Ile	missense	Exon 4 of 21	ENSP00000258123.4	Q9Y4E8-2
	USP15	ENST00000312635.10	TSL:1	c.446C>T	p.Thr149Ile	missense	Exon 4 of 7	ENSP00000309240.6	Q9Y4E8-4

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 151976 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

GnomAD2 exomes AF: 0.00000849 AC: 2 AN: 235554 AF XY: 0.00000782

Gnomad AFR exome AF: 0.0000664

Gnomad AMR exome AF: 0.0000332

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000278 AC: 4 AN: 1439438 Hom.: 0 Cov.: 30 AF XY: 0.00000279 AC XY: 2 AN XY: 715944

African (AFR) AF: 0.0000309 AC: 1 AN: 32372

American (AMR) AF: 0.0000729 AC: 3 AN: 41170

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25666

East Asian (EAS) AF: 0.00 AC: 0 AN: 38248

South Asian (SAS) AF: 0.00 AC: 0 AN: 82820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52838

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1101270

Other (OTH) AF: 0.00 AC: 0 AN: 59348

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 151976 Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4 AN XY: 74206

African (AFR) AF: 0.000145 AC: 6 AN: 41428

American (AMR) AF: 0.000131 AC: 2 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67870

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000336 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Benign	0.15
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.3
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.18
Sift	Benign	0.066	T
Sift4G	Benign	0.27	T
Polyphen		0.99	D
Vest4		0.30
MutPred		0.67		Loss of phosphorylation at T149 (P = 0.0545)
MVP		0.35
MPC		1.1
ClinPred		0.53	D
GERP RS		4.5
Varity_R		0.65
gMVP		0.66
Mutation Taster		=34/66	disease causing

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

Other links and lift over

dbSNP: rs753767001; hg19: chr12-62708668;