12-6852190-T-C

Position:

• chr12-6852190-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001098536.2(USP5):​c.11T>C​(p.Leu4Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: USP5 NM_001098536.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.64

Genes affected

USP5 (HGNC:12628): (ubiquitin specific peptidase 5) Ubiquitin (see MIM 191339)-dependent proteolysis is a complex pathway of protein metabolism implicated in such diverse cellular functions as maintenance of chromatin structure, receptor function, and degradation of abnormal proteins. A late step of the process involves disassembly of the polyubiquitin chains on degraded proteins into ubiquitin monomers. USP5 disassembles branched polyubiquitin chains by a sequential exo mechanism, starting at the proximal end of the chain (Wilkinson et al., 1995 [PubMed 7578059]).[supplied by OMIM, Mar 2010]

USP5 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37362733).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP5	NM_001098536.2	c.11T>C	p.Leu4Pro	missense_variant	1/20	ENST00000229268.13	NP_001092006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP5	ENST00000229268.13	c.11T>C	p.Leu4Pro	missense_variant	1/20	1	NM_001098536.2	ENSP00000229268.8
USP5	ENST00000389231.9	c.11T>C	p.Leu4Pro	missense_variant	1/20	1		ENSP00000373883.5
USP5	ENST00000542087.1	c.11T>C	p.Leu4Pro	missense_variant	1/5	3		ENSP00000444668.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

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

Jan 26, 2022

The c.11T>C (p.L4P) alteration is located in exon 1 (coding exon 1) of the USP5 gene. This alteration results from a T to C substitution at nucleotide position 11, causing the leucine (L) at amino acid position 4 to be replaced by a proline (P). 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	0.22
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T;.;.
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.37	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;N;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.67	N;N;N
REVEL	Benign	0.13
Sift	Uncertain	0.0090	D;D;D
Sift4G	Uncertain	0.033	D;D;T
Polyphen		0.97	D;D;.
Vest4		0.53
MutPred		0.33		Gain of disorder (P = 0.0126);Gain of disorder (P = 0.0126);Gain of disorder (P = 0.0126);
MVP		0.22
MPC		1.1
ClinPred		0.90	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.76
gMVP		0.92

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: chr12-6961354;