rs5030732

Positions:

chr4-41257616-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004181.5(UCHL1):c.53C>A(p.Ser18Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.192 in 1,550,242 control chromosomes in the GnomAD database, including 33,472 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 2985 hom., cov: 33)

Exomes 𝑓: 0.19 ( 30487 hom. )

Consequence

UCHL1
NM_004181.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:8

Conservation

PhyloP100: 1.06

Variant links:

Genes affected

UCHL1 (HGNC:12513): (ubiquitin C-terminal hydrolase L1) The protein encoded by this gene belongs to the peptidase C12 family. This enzyme is a thiol protease that hydrolyzes a peptide bond at the C-terminal glycine of ubiquitin. This gene is specifically expressed in the neurons and in cells of the diffuse neuroendocrine system. Mutations in this gene may be associated with Parkinson disease.[provided by RefSeq, Sep 2009]

UCHL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.282443E-5).

BP6

Variant 4-41257616-C-A is Benign according to our data. Variant chr4-41257616-C-A is described in ClinVar as [Benign]. Clinvar id is 12298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-41257616-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.504 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UCHL1	NM_004181.5 linkuse as main transcript	c.53C>A	p.Ser18Tyr	missense_variant	3/9	ENST00000284440.9	NP_004172.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UCHL1	ENST00000284440.9 linkuse as main transcript	c.53C>A	p.Ser18Tyr	missense_variant	3/9	1	NM_004181.5	ENSP00000284440	P1

Frequencies

GnomAD3 genomes

AF:

0.166

AC:

25316

AN:

152054

Hom.:

2979

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0407

Gnomad AMI

AF:

0.166

Gnomad AMR

AF:

0.264

Gnomad ASJ

AF:

0.217

Gnomad EAS

AF:

0.521

Gnomad SAS

AF:

0.320

Gnomad FIN

AF:

0.147

Gnomad MID

AF:

0.197

Gnomad NFE

AF:

0.184

Gnomad OTH

AF:

0.161

GnomAD3 exomes

AF:

0.242

AC:

37510

AN:

154918

Hom.:

5650

AF XY:

0.242

AC XY:

20429

AN XY:

84480

show subpopulations

Gnomad AFR exome

AF:

0.0328

Gnomad AMR exome

AF:

0.319

Gnomad ASJ exome

AF:

0.209

Gnomad EAS exome

AF:

0.531

Gnomad SAS exome

AF:

0.306

Gnomad FIN exome

AF:

0.143

Gnomad NFE exome

AF:

0.179

Gnomad OTH exome

AF:

0.224

GnomAD4 exome

AF:

0.195

AC:

272507

AN:

1398072

Hom.:

30487

Cov.:

AF XY:

0.198

AC XY:

137028

AN XY:

691480

show subpopulations

Gnomad4 AFR exome

AF:

0.0320

Gnomad4 AMR exome

AF:

0.311

Gnomad4 ASJ exome

AF:

0.220

Gnomad4 EAS exome

AF:

0.519

Gnomad4 SAS exome

AF:

0.307

Gnomad4 FIN exome

AF:

0.151

Gnomad4 NFE exome

AF:

0.177

Gnomad4 OTH exome

AF:

0.205

GnomAD4 genome

AF:

0.167

AC:

25340

AN:

152170

Hom.:

2985

Cov.:

AF XY:

0.171

AC XY:

12709

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.0409

Gnomad4 AMR

AF:

0.265

Gnomad4 ASJ

AF:

0.217

Gnomad4 EAS

AF:

0.520

Gnomad4 SAS

AF:

0.320

Gnomad4 FIN

AF:

0.147

Gnomad4 NFE

AF:

0.184

Gnomad4 OTH

AF:

0.163

Alfa

AF:

0.178

Hom.:

909

Bravo

AF:

0.171

TwinsUK

AF:

0.183

AC:

678

ALSPAC

AF:

0.177

AC:

684

ESP6500AA

AF:

0.0273

AC:

114

ESP6500EA

AF:

0.135

AC:

1114

ExAC

AF:

0.171

AC:

19411

Asia WGS

AF:

0.383

AC:

1329

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Parkinson disease 5, autosomal dominant, susceptibility to

Uncertain:1Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Feb 07, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Jun 01, 2011	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 20, 2021	This variant is associated with the following publications: (PMID: 12705903, 21700325, 19864305, 19683447, 21251915, 21298373, 18411255, 22076440, 21268678, 17287139, 25370916, 10563640, 33028204, 12408865) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.14

.;T;T;.;T

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.42

T;.;T;T;T

MetaRNN

Benign

0.000083

T;T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.3

.;L;L;.;.

MutationTaster

Benign

0.073

P;P;P;P

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.9

N;N;N;N;N

REVEL

Benign

0.052

Sift

Benign

0.072

T;T;T;T;T

Sift4G

Uncertain

0.022

D;T;T;T;T

Polyphen

0.63

.;P;P;.;.

Vest4

0.16, 0.16, 0.23, 0.11

MPC

0.83

ClinPred

0.017

GERP RS

2.8

Varity_R

0.46

gMVP

0.48

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over