4-41257132-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_004181.5(UCHL1):c.45+6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0658 in 1,612,630 control chromosomes in the GnomAD database, including 3,993 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.051 ( 283 hom., cov: 33)

Exomes 𝑓: 0.067 ( 3710 hom. )

Consequence

UCHL1
NM_004181.5 splice_region, intron

Scores

Splicing: ADA: 0.8166

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.22

Publications

6 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 -16 ACMG points.

BP6

Variant 4-41257132-T-C is Benign according to our data. Variant chr4-41257132-T-C is described in CliVar as Benign. Clinvar id is 348769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-41257132-T-C is described in CliVar as Benign. Clinvar id is 348769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-41257132-T-C is described in CliVar as Benign. Clinvar id is 348769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-41257132-T-C is described in CliVar as Benign. Clinvar id is 348769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-41257132-T-C is described in CliVar as Benign. Clinvar id is 348769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-41257132-T-C is described in CliVar as Benign. Clinvar id is 348769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-41257132-T-C is described in CliVar as Benign. Clinvar id is 348769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-41257132-T-C is described in CliVar as Benign. Clinvar id is 348769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-41257132-T-C is described in CliVar as Benign. Clinvar id is 348769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-41257132-T-C is described in CliVar as Benign. Clinvar id is 348769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-41257132-T-C is described in CliVar as Benign. Clinvar id is 348769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-41257132-T-C is described in CliVar as Benign. Clinvar id is 348769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-41257132-T-C is described in CliVar as Benign. Clinvar id is 348769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0792 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UCHL1	NM_004181.5 link	c.45+6T>C		splice_region_variant, intron_variant	Intron 2 of 8	ENST00000284440.9	NP_004172.2	P09936V9HW74

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UCHL1	ENST00000284440.9 link	c.45+6T>C		splice_region_variant, intron_variant	Intron 2 of 8	1	NM_004181.5	ENSP00000284440.4		P09936

Frequencies

GnomAD3 genomes

AF:

0.0514

AC:

7819

AN:

152062

Hom.:

284

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0161

Gnomad AMI

AF:

0.0329

Gnomad AMR

AF:

0.0567

Gnomad ASJ

AF:

0.0326

Gnomad EAS

AF:

0.000775

Gnomad SAS

AF:

0.0116

Gnomad FIN

AF:

0.0366

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.0810

Gnomad OTH

AF:

0.0746

GnomAD2 exomes

AF:

0.0525

AC:

13140

AN:

250096

AF XY:

0.0533

show subpopulations

Gnomad AFR exome

AF:

0.0166

Gnomad AMR exome

AF:

0.0447

Gnomad ASJ exome

AF:

0.0359

Gnomad EAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.0379

Gnomad NFE exome

AF:

0.0824

Gnomad OTH exome

AF:

0.0644

GnomAD4 exome

AF:

0.0673

AC:

98305

AN:

1460452

Hom.:

3710

Cov.:

AF XY:

0.0664

AC XY:

48238

AN XY:

726470

show subpopulations

African (AFR)

AF:

0.0146

AC:

488

AN:

33422

American (AMR)

AF:

0.0460

AC:

2059

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0360

AC:

940

AN:

26128

East Asian (EAS)

AF:

0.000202

AC:

AN:

39694

South Asian (SAS)

AF:

0.0148

AC:

1272

AN:

86198

European-Finnish (FIN)

AF:

0.0387

AC:

2061

AN:

53244

Middle Eastern (MID)

AF:

0.101

AC:

494

AN:

4878

European-Non Finnish (NFE)

AF:

0.0784

AC:

87177

AN:

1111894

Other (OTH)

AF:

0.0631

AC:

3806

AN:

60276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

5880

11760

17641

23521

29401

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3048

6096

9144

12192

15240

<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:

0.0513

AC:

7813

AN:

152178

Hom.:

283

Cov.:

AF XY:

0.0483

AC XY:

3595

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.0160

AC:

665

AN:

41510

American (AMR)

AF:

0.0565

AC:

865

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0326

AC:

113

AN:

3470

East Asian (EAS)

AF:

0.000777

AC:

AN:

5148

South Asian (SAS)

AF:

0.0118

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0366

AC:

388

AN:

10610

Middle Eastern (MID)

AF:

0.0850

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0810

AC:

5510

AN:

68000

Other (OTH)

AF:

0.0739

AC:

156

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

372

744

1116

1488

1860

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

200

300

400

500

<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:

0.0677

Hom.:

295

Bravo

AF:

0.0513

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.0860

EpiControl

AF:

0.0895

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 24, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Parkinson disease 5, autosomal dominant, susceptibility to

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.93

PhyloP100

2.2

PromoterAI

-0.17

Neutral

(source)

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.82

dbscSNV1_RF

Pathogenic

0.72

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.22

Position offset: -6

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