13-75566726-A-G

Variant summary

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

The NM_006002.5(UCHL3):c.215A>G(p.Lys72Arg) 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: UCHL3 NM_006002.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.25

Genes affected

UCHL3 (HGNC:12515): (ubiquitin C-terminal hydrolase L3) The protein encoded by this gene is a member of the deubiquitinating enzyme family. Members of this family are proteases that catalyze the removal of ubiquitin from polypeptides and are divided into five classes, depending on the mechanism of catalysis. This protein may hydrolyze the ubiquitinyl-N-epsilon amide bond of ubiquitinated proteins to regenerate ubiquitin for another catalytic cycle. Alternative splicing results in multiple transcript variants that encode different protein isoforms. [provided by RefSeq, Aug 2012]

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=0.13608679).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UCHL3	NM_006002.5	c.215A>G	p.Lys72Arg	missense_variant	4/9	ENST00000377595.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UCHL3	ENST00000377595.8	c.215A>G	p.Lys72Arg	missense_variant	4/9	1	NM_006002.5	P1
UCHL3	ENST00000419068.1	c.17A>G	p.Lys6Arg	missense_variant	1/7	5
UCHL3	ENST00000471792.6	n.361A>G		non_coding_transcript_exon_variant	4/7	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Jul 07, 2022

The c.215A>G (p.K72R) alteration is located in exon 4 (coding exon 4) of the UCHL3 gene. This alteration results from a A to G substitution at nucleotide position 215, causing the lysine (K) at amino acid position 72 to be replaced by an arginine (R). 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	0.067
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	19
Dann	Uncertain	0.99
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.89	D;D;T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.59	T
Sift4G	Benign	0.53	T;T;T
Polyphen		0.0010	.;B;.
Vest4		0.062
MutPred		0.36		.;Loss of ubiquitination at K72 (P = 0.0019);.;
MVP		0.50
MPC		0.24
ClinPred		0.67	D
GERP RS		4.6
Varity_R		0.21
gMVP		0.22

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: chr13-76140862;