rs1057519600

Positions:

• chr4-41268048-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_004181.5(UCHL1):​c.647C>A​(p.Ala216Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: UCHL1 NM_004181.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.98

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.852
• PP5: Variant 4-41268048-C-A is Pathogenic according to our data. Variant chr4-41268048-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 375650.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.647C>A	p.Ala216Asp	missense_variant	9/9	ENST00000284440.9	NP_004172.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UCHL1	ENST00000284440.9	c.647C>A	p.Ala216Asp	missense_variant	9/9	1	NM_004181.5	ENSP00000284440.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	25
DANN	Benign	0.92
DEOGEN2	Uncertain	0.54	D;D;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.97	.;D;D
M_CAP	Benign	0.073	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.5	M;M;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-4.1	.;D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0030	.;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.98	D;D;.
Vest4		0.92
MutPred		0.64		Loss of MoRF binding (P = 0.0454);Loss of MoRF binding (P = 0.0454);.;
MVP		0.92
MPC		1.9
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.91
gMVP		0.84

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: rs1057519600; hg19: chr4-41270065;