rs4861387

Variant names:

• chr4-41266448-G-A
• rs4861387
• NM_004181.5:c.586-1539G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004181.5(UCHL1):​c.586-1539G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 151,884 control chromosomes in the GnomAD database, including 3,707 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.21 (3707 hom., cov: 31)
• Consequence: UCHL1 NM_004181.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.187
• 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):

• hereditary spastic paraplegia

  Inheritance: AR, AD Classification: DEFINITIVE, MODERATE Submitted by: ClinGen
• spastic paraplegia 79A, autosomal dominant, with ataxia

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

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

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.232 is higher than 0.05.

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.586-1539G>A		intron	N/A	NP_004172.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UCHL1	ENST00000284440.9	TSL:1 MANE Select	c.586-1539G>A		intron	N/A	ENSP00000284440.4	P09936-1
	UCHL1	ENST00000512788.1	TSL:3	c.615-1539G>A		intron	N/A	ENSP00000423623.1	D6R956
	UCHL1	ENST00000503431.5	TSL:3	c.586-1539G>A		intron	N/A	ENSP00000422542.1	P09936-1

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32588 AN: 151766 Hom.: 3704 Cov.: 31

Gnomad AFR AF: 0.236

Gnomad AMI AF: 0.402

Gnomad AMR AF: 0.169

Gnomad ASJ AF: 0.217

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.0935

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.231

Gnomad OTH AF: 0.224

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.215 AC: 32611 AN: 151884 Hom.: 3707 Cov.: 31 AF XY: 0.209 AC XY: 15535 AN XY: 74228

African (AFR) AF: 0.236 AC: 9764 AN: 41394

American (AMR) AF: 0.169 AC: 2584 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.217 AC: 752 AN: 3470

East Asian (EAS) AF: 0.109 AC: 563 AN: 5164

South Asian (SAS) AF: 0.0931 AC: 448 AN: 4810

European-Finnish (FIN) AF: 0.179 AC: 1886 AN: 10540

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.231 AC: 15720 AN: 67930

Other (OTH) AF: 0.224 AC: 471 AN: 2104

Alfa AF: 0.217 Hom.: 2529

Bravo AF: 0.218

Asia WGS AF: 0.117 AC: 406 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.0
DANN	Benign	0.58
PhyloP100		-0.19
Mutation Taster		=100/0	polymorphism (auto)

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: rs4861387; hg19: chr4-41268465;