4-41256953-A-G

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.-24A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.095 in 1,613,688 control chromosomes in the GnomAD database, including 8,016 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (889 hom., cov: 33)
  • Exomes 𝑓: 0.094 (7127 hom.)
• Consequence: UCHL1 NM_004181.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.100

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 (BayesDel_noAF=-0.79).
• BP6: Variant 4-41256953-A-G is Benign according to our data. Variant chr4-41256953-A-G is described in ClinVar as [Benign]. Clinvar id is 348766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.144 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UCHL1	NM_004181.5	c.-24A>G		5_prime_UTR_variant	1/9	ENST00000284440.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UCHL1	ENST00000284440.9	c.-24A>G		5_prime_UTR_variant	1/9	1	NM_004181.5	P1

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15602 AN: 152004 Hom.: 887 Cov.: 33

Gnomad AFR AF: 0.0855

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.153

Gnomad SAS AF: 0.0804

Gnomad FIN AF: 0.213

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0915

Gnomad OTH AF: 0.0947

GnomAD3 exomes AF: 0.113 AC: 28459 AN: 250896 Hom.: 1793 AF XY: 0.109 AC XY: 14762 AN XY: 135788

Gnomad AFR exome AF: 0.0867

Gnomad AMR exome AF: 0.146

Gnomad ASJ exome AF: 0.109

Gnomad EAS exome AF: 0.155

Gnomad SAS exome AF: 0.0826

Gnomad FIN exome AF: 0.208

Gnomad NFE exome AF: 0.0918

Gnomad OTH exome AF: 0.108

GnomAD4 exome AF: 0.0942 AC: 137714 AN: 1461564 Hom.: 7127 Cov.: 32 AF XY: 0.0932 AC XY: 67748 AN XY: 727104

Gnomad4 AFR exome AF: 0.0851

Gnomad4 AMR exome AF: 0.142

Gnomad4 ASJ exome AF: 0.108

Gnomad4 EAS exome AF: 0.148

Gnomad4 SAS exome AF: 0.0832

Gnomad4 FIN exome AF: 0.201

Gnomad4 NFE exome AF: 0.0860

Gnomad4 OTH exome AF: 0.0966

GnomAD4 genome AF: 0.103 AC: 15606 AN: 152124 Hom.: 889 Cov.: 33 AF XY: 0.108 AC XY: 8066 AN XY: 74352

Gnomad4 AFR AF: 0.0852

Gnomad4 AMR AF: 0.108

Gnomad4 ASJ AF: 0.109

Gnomad4 EAS AF: 0.153

Gnomad4 SAS AF: 0.0811

Gnomad4 FIN AF: 0.213

Gnomad4 NFE AF: 0.0916

Gnomad4 OTH AF: 0.0942

Alfa AF: 0.0700 Hom.: 103

Bravo AF: 0.0968

Asia WGS AF: 0.106 AC: 368 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	11
Dann	Benign	0.53

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: rs11556271; hg19: chr4-41258970; COSMIC: COSV52650999; COSMIC: COSV52650999;