NM_004181.5:c.533G>A

Variant names:

• chr4-41264109-G-A
• rs768996179
• NM_004181.5:c.533G>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3 BS1_Supporting BS2

The NM_004181.5(UCHL1):​c.533G>A​(p.Arg178Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000226 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: UCHL1 NM_004181.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 8.02

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 Likely_benign. Variant got -4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.835
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000226 (33/1461888) while in subpopulation SAS AF= 0.0000812 (7/86258). AF 95% confidence interval is 0.0000376. There are 0 homozygotes in gnomad4_exome. There are 23 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 33 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UCHL1	NM_004181.5	c.533G>A	p.Arg178Gln	missense_variant	Exon 8 of 9	ENST00000284440.9	NP_004172.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UCHL1	ENST00000284440.9	c.533G>A	p.Arg178Gln	missense_variant	Exon 8 of 9	1	NM_004181.5	ENSP00000284440.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000517 AC: 13 AN: 251496 Hom.: 0 AF XY: 0.0000662 AC XY: 9 AN XY: 135922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000791

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000226 AC: 33 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.0000316 AC XY: 23 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.0000824 AC: 10

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jan 27, 2023

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.59	D;D;.;T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	.;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.83	D;D;D;D
MetaSVM	Uncertain	0.030	D
MutationAssessor	Pathogenic	3.7	H;H;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.1	D;D;D;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0050	D;D;D;D
Sift4G	Uncertain	0.011	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.75
MutPred		0.66		Loss of methylation at R178 (P = 0.0475);Loss of methylation at R178 (P = 0.0475);.;Loss of methylation at R178 (P = 0.0475);
MVP		0.75
MPC		1.5
ClinPred		0.78	D
GERP RS		5.5
Varity_R		0.87
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs768996179; hg19: chr4-41266126;