4-41257616-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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

Publications

157 publications found

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 Gene-Disease associations (from GenCC):

spastic paraplegia 79A, autosomal dominant, with ataxia
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
Parkinson disease 5, autosomal dominant, susceptibility to
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

UCHL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 12298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
UCHL1	NM_004181.5 link	c.53C>A	p.Ser18Tyr	missense_variant	Exon 3 of 9	ENST00000284440.9	NP_004172.2	P09936V9HW74

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UCHL1	ENST00000284440.9 link	c.53C>A	p.Ser18Tyr	missense_variant	Exon 3 of 9	1	NM_004181.5	ENSP00000284440.4		P09936

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

GnomAD2 exomes

AF:

0.242

AC:

37510

AN:

154918

AF XY:

0.242

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 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

African (AFR)

AF:

0.0320

AC:

1007

AN:

31490

American (AMR)

AF:

0.311

AC:

11608

AN:

37364

Ashkenazi Jewish (ASJ)

AF:

0.220

AC:

5509

AN:

25076

East Asian (EAS)

AF:

0.519

AC:

18877

AN:

36394

South Asian (SAS)

AF:

0.307

AC:

24362

AN:

79478

European-Finnish (FIN)

AF:

0.151

AC:

6029

AN:

39894

Middle Eastern (MID)

AF:

0.217

AC:

936

AN:

4312

European-Non Finnish (NFE)

AF:

0.177

AC:

192241

AN:

1085878

Other (OTH)

AF:

0.205

AC:

11938

AN:

58186

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

12330

24661

36991

49322

61652

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7058

14116

21174

28232

35290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.167

AC:

25340

AN:

152170

Hom.:

2985

Cov.:

AF XY:

0.171

AC XY:

12709

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.0409

AC:

1701

AN:

41570

American (AMR)

AF:

0.265

AC:

4060

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.217

AC:

751

AN:

3464

East Asian (EAS)

AF:

0.520

AC:

2671

AN:

5132

South Asian (SAS)

AF:

0.320

AC:

1544

AN:

4824

European-Finnish (FIN)

AF:

0.147

AC:

1563

AN:

10618

Middle Eastern (MID)

AF:

0.193

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.184

AC:

12501

AN:

67960

Other (OTH)

AF:

0.163

AC:

342

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

1010

2021

3031

4042

5052

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

290

580

870

1160

1450

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.189

Hom.:

1682

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

Jun 01, 2011

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 07, 2015

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:3

Apr 20, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 12705903, 21700325, 19864305, 19683447, 21251915, 21298373, 18411255, 22076440, 21268678, 17287139, 25370916, 10563640, 33028204, 12408865) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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;.;.

PhyloP100

1.1

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

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over