rs5030732

Variant names:

Your query was ambiguous. Multiple possible variants found:

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):

hereditary spastic paraplegia
Inheritance: AD, AR Classification: DEFINITIVE, MODERATE Submitted by: ClinGen
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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004181.5. 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
	UCHL1	NM_004181.5	MANE Select	c.53C>A	p.Ser18Tyr	missense	Exon 3 of 9	NP_004172.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
UCHL1	ENST00000284440.9	TSL:1 MANE Select	c.53C>A	p.Ser18Tyr	missense	Exon 3 of 9	ENSP00000284440.4	P09936-1
UCHL1	ENST00000512788.1	TSL:3	c.53C>A	p.Ser18Tyr	missense	Exon 3 of 9	ENSP00000423623.1	D6R956
UCHL1	ENST00000503431.5	TSL:3	c.53C>A	p.Ser18Tyr	missense	Exon 4 of 10	ENSP00000422542.1	P09936-1

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Parkinson disease 5, autosomal dominant, susceptibility to (5)

not provided (3)

Early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome (1)

Computational scores

Source: dbNSFP v4.9

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

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.42

MetaRNN

Benign

0.000083

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.3

PhyloP100

1.1

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.9

REVEL

Benign

0.052

Sift

Benign

0.072

Sift4G

Uncertain

0.022

Polyphen

0.63

Vest4

0.16

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over