4-41257616-C-G

Variant names:

• chr4-41257616-C-G
• rs5030732
• NM_004181.5:c.53C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004181.5(UCHL1):​c.53C>G​(p.Ser18Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S18Y) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: UCHL1 NM_004181.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.06
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• spastic paraplegia 79A, autosomal dominant, with ataxia

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• Parkinson disease 5, autosomal dominant, susceptibility to

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16365865).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UCHL1	NM_004181.5	c.53C>G	p.Ser18Cys	missense_variant	Exon 3 of 9	ENST00000284440.9	NP_004172.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UCHL1	ENST00000284440.9	c.53C>G	p.Ser18Cys	missense_variant	Exon 3 of 9	1	NM_004181.5	ENSP00000284440.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	19
DANN	Benign	0.91
DEOGEN2	Benign	0.37	.;T;T;.;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.80	T;.;T;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.16	T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.1	.;L;L;.;.
PhyloP100		1.1
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.8	D;D;D;N;D
REVEL	Benign	0.057
Sift	Benign	0.060	T;T;T;T;T
Sift4G	Benign	0.099	T;T;T;T;T
Polyphen		0.0	.;B;B;.;.
Vest4		0.31, 0.30, 0.34, 0.29
MutPred		0.39		Loss of MoRF binding (P = 0.0662);Loss of MoRF binding (P = 0.0662);Loss of MoRF binding (P = 0.0662);Loss of MoRF binding (P = 0.0662);Loss of MoRF binding (P = 0.0662);
MVP		0.22
MPC		0.56
ClinPred		0.19	T
GERP RS		2.8
Varity_R		0.39
gMVP		0.37
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs5030732; hg19: chr4-41259633;