4-41256999-T-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BS1

The NM_004181.5(UCHL1):​c.23T>G​(p.Ile8Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,790 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. I8T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: UCHL1 NM_004181.5 missense
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.00000205 (3/1461790) while in subpopulation AFR AF = 0.0000597 (2/33480). AF 95% confidence interval is 0.00000989. There are 0 homozygotes in GnomAdExome4. There are 3 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

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>G	p.Ile8Ser	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>G	p.Ile8Ser	missense	Exon 1 of 9	ENSP00000284440.4	P09936-1
	UCHL1	ENST00000512788.1	TSL:3	c.23T>G	p.Ile8Ser	missense	Exon 1 of 9	ENSP00000423623.1	D6R956
	UCHL1	ENST00000503431.5	TSL:3	c.23T>G	p.Ile8Ser	missense	Exon 2 of 10	ENSP00000422542.1	P09936-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461790 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727188

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111980

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.064	T
Eigen	Benign	0.15
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.56	N
PhyloP100		3.5
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	0.52	N
REVEL	Benign	0.24
Sift	Benign	0.63	T
Sift4G	Benign	0.14	T
Polyphen		1.0	D
Vest4		0.75
MutPred		0.57		Gain of disorder (P = 0.0023)
MVP		0.61
MPC		1.9
ClinPred		0.74	D
GERP RS		4.8
PromoterAI		-0.14	Neutral
Varity_R		0.47
gMVP		0.65
Mutation Taster		=71/29	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;