chr4-41256999-TC-T

Position:

• chr4-41256999-TC-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_004181.5(UCHL1):​c.24delC​(p.Asn9fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: UCHL1 NM_004181.5 frameshift
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.0490

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.964 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-41256999-TC-T is Pathogenic according to our data. Variant chr4-41256999-TC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3345701.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UCHL1	NM_004181.5	c.24delC	p.Asn9fs	frameshift_variant	1/9	ENST00000284440.9	NP_004172.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UCHL1	ENST00000284440.9	c.24delC	p.Asn9fs	frameshift_variant	1/9	1	NM_004181.5	ENSP00000284440.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

UCHL1-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 28, 2024

The UCHL1 c.24delC variant is predicted to result in a frameshift and premature protein termination (p.Asn9Thrfs*5). To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. Loss of function variants, such as this frameshift variant, in UCHL1 are an established mechanism of autosomal dominant disease (Park et al. 2022. PubMed ID: 35986737). Of note, an upstream loss-of-function variant has been reported as causative (Park et al. 2022. PubMed ID: 35986737). Given the evidence, we interpret this variant as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-41259016;