chr4-41256961-C-T

Variant names:

• chr4-41256961-C-T
• rs9321
• NM_004181.5:c.-16C>T

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.-16C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0948 in 1,613,892 control chromosomes in the GnomAD database, including 7,986 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (874 hom., cov: 33)
  • Exomes 𝑓: 0.094 (7112 hom.)
• Consequence: UCHL1 NM_004181.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.53

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-DT (HGNC:40600): (UCHL1 divergent transcript)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 4-41256961-C-T is Benign according to our data. Variant chr4-41256961-C-T is described in ClinVar as [Benign]. Clinvar id is 348767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-41256961-C-T is described in Lovd as [Benign].
• 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 rank	MANE	Protein	UniProt
UCHL1	NM_004181.5	c.-16C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 9	ENST00000284440.9	NP_004172.2
UCHL1	NM_004181.5	c.-16C>T		5_prime_UTR_variant	Exon 1 of 9	ENST00000284440.9	NP_004172.2
UCHL1-DT	NR_102709.1	n.-234G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UCHL1	ENST00000284440	c.-16C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 9	1	NM_004181.5	ENSP00000284440.4
UCHL1	ENST00000284440	c.-16C>T		5_prime_UTR_variant	Exon 1 of 9	1	NM_004181.5	ENSP00000284440.4

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15396 AN: 152130 Hom.: 872 Cov.: 33

Gnomad AFR AF: 0.0804

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.152

Gnomad SAS AF: 0.0809

Gnomad FIN AF: 0.212

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0917

Gnomad OTH AF: 0.0939

GnomAD3 exomes AF: 0.113 AC: 28397 AN: 250904 Hom.: 1796 AF XY: 0.109 AC XY: 14755 AN XY: 135796

Gnomad AFR exome AF: 0.0819

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: 0.0919

Gnomad OTH exome AF: 0.107

GnomAD4 exome AF: 0.0941 AC: 137534 AN: 1461642 Hom.: 7112 Cov.: 32 AF XY: 0.0931 AC XY: 67667 AN XY: 727138

Gnomad4 AFR exome AF: 0.0802

Gnomad4 AMR exome AF: 0.141

Gnomad4 ASJ exome AF: 0.108

Gnomad4 EAS exome AF: 0.148

Gnomad4 SAS exome AF: 0.0831

Gnomad4 FIN exome AF: 0.201

Gnomad4 NFE exome AF: 0.0860

Gnomad4 OTH exome AF: 0.0965

GnomAD4 genome AF: 0.101 AC: 15400 AN: 152250 Hom.: 874 Cov.: 33 AF XY: 0.107 AC XY: 7966 AN XY: 74424

Gnomad4 AFR AF: 0.0801

Gnomad4 AMR AF: 0.108

Gnomad4 ASJ AF: 0.109

Gnomad4 EAS AF: 0.153

Gnomad4 SAS AF: 0.0815

Gnomad4 FIN AF: 0.212

Gnomad4 NFE AF: 0.0917

Gnomad4 OTH AF: 0.0934

Alfa AF: 0.0869 Hom.: 854

Bravo AF: 0.0952

Asia WGS AF: 0.106 AC: 367 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Apr 19, 2021

GeneDx

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

- -

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	-0.87
CADD	Benign	0.041
DANN	Benign	0.83

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: rs9321; hg19: chr4-41258978; COSMIC: COSV52651008; COSMIC: COSV52651008;