rs5030732

Positions:

• chr4-41257616-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:7
• Conservation: PhyloP100: 1.06

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]

ACMG classification

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	UniProt
UCHL1	NM_004181.5	c.53C>A	p.Ser18Tyr	missense_variant	3/9	ENST00000284440.9

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25316 AN: 152054 Hom.: 2979 Cov.: 33

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

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.: 33 AF XY: 0.198 AC XY: 137028 AN XY: 691480

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.: 33 AF XY: 0.171 AC XY: 12709 AN XY: 74404

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:1 Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Parkinson disease 5, autosomal dominant, susceptibility to Uncertain:1 Benign:4

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Feb 07, 2015	- -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Jun 01, 2011	- -
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, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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) -

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	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Benign	0.96
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.42	T;.;T;T;T
MetaRNN	Benign	0.000083	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	0.073	P;P;P;P
PrimateAI	Benign	0.45	T
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	T
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

Other links and lift over

dbSNP: rs5030732; hg19: chr4-41259633; COSMIC: COSV52651628; COSMIC: COSV52651628;