NM_004181.5:c.647C>A

Variant names:

• chr4-41268048-C-A
• rs1057519600
• NM_004181.5:c.647C>A

Variant summary

Our verdict is Uncertain significance. The variant received 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). Synonymous variant affecting the same amino acid position (i.e. A216A) has been classified as Likely benign.

• 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
• Publications: 6 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 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 VariationId is 375650.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UCHL1	NM_004181.5	c.647C>A	p.Ala216Asp	missense_variant	Exon 9 of 9	ENST00000284440.9	NP_004172.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UCHL1	ENST00000284440.9	c.647C>A	p.Ala216Asp	missense_variant	Exon 9 of 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

Jan 27, 2023

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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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;.
PhyloP100		4.0
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
Mutation Taster		=8/92	disease causing (ClinVar)

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: rs1057519600; hg19: chr4-41270065;