4-41256999-T-C

Variant names:

• chr4-41256999-T-C
• rs1780984927
• NM_004181.5:c.23T>C

Variant summary

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

The NM_004181.5(UCHL1):​c.23T>C​(p.Ile8Thr) variant causes a missense 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: UCHL1 NM_004181.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.46
• 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):

• hereditary spastic paraplegia

  Inheritance: AD, AR Classification: DEFINITIVE, MODERATE Submitted by: ClinGen
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004181.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UCHL1	NM_004181.5	MANE Select	c.23T>C	p.Ile8Thr	missense	Exon 1 of 9	NP_004172.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UCHL1	ENST00000284440.9	TSL:1 MANE Select	c.23T>C	p.Ile8Thr	missense	Exon 1 of 9	ENSP00000284440.4	P09936-1
	UCHL1	ENST00000512788.1	TSL:3	c.23T>C	p.Ile8Thr	missense	Exon 1 of 9	ENSP00000423623.1	D6R956
	UCHL1	ENST00000503431.5	TSL:3	c.23T>C	p.Ile8Thr	missense	Exon 2 of 10	ENSP00000422542.1	P09936-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.082	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		3.5
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.19	N
REVEL	Uncertain	0.32
Sift	Benign	0.55	T
Sift4G	Uncertain	0.020	D
Polyphen		1.0	D
Vest4		0.65
MutPred		0.57		Gain of disorder (P = 0.0196)
MVP		0.48
MPC		1.7
ClinPred		0.90	D
GERP RS		4.8
PromoterAI		-0.041	Neutral
Varity_R		0.50
gMVP		0.52
Mutation Taster		=73/27	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: rs1780984927; hg19: chr4-41259016;