chr4-41257096-C-T

Variant names:

• chr4-41257096-C-T
• rs6832687
• NM_004181.5:c.34-19C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004181.5(UCHL1):​c.34-19C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00239 in 1,613,794 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (36 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (37 hom.)
• Consequence: UCHL1 NM_004181.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.641

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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 4-41257096-C-T is Benign according to our data. Variant chr4-41257096-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1316120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0114 (1742/152330) while in subpopulation AFR AF = 0.0382 (1588/41584). AF 95% confidence interval is 0.0366. There are 36 homozygotes in GnomAd4. There are 807 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position FAILED quality control check.
• BS2: High AC in GnomAd4 at 1742 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UCHL1	NM_004181.5	c.34-19C>T		intron_variant	Intron 1 of 8	ENST00000284440.9	NP_004172.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UCHL1	ENST00000284440.9	c.34-19C>T		intron_variant	Intron 1 of 8	1	NM_004181.5	ENSP00000284440.4

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1735 AN: 152212 Hom.: 36 Cov.: 33

Gnomad AFR AF: 0.0381

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00674

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00907

GnomAD2 exomes AF: 0.00329 AC: 828 AN: 251314 AF XY: 0.00255

Gnomad AFR exome AF: 0.0387

Gnomad AMR exome AF: 0.00292

Gnomad ASJ exome AF: 0.00347

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000317

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00145 AC: 2120 AN: 1461464 Hom.: 37 Cov.: 32 AF XY: 0.00137 AC XY: 995 AN XY: 727052

Gnomad4 AFR exome AF: 0.0431 AC: 1441 AN: 33468

Gnomad4 AMR exome AF: 0.00302 AC: 135 AN: 44722

Gnomad4 ASJ exome AF: 0.00283 AC: 74 AN: 26128

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39696

Gnomad4 SAS exome AF: 0.000104 AC: 9 AN: 86240

Gnomad4 FIN exome AF: 0.000131 AC: 7 AN: 53348

Gnomad4 NFE exome AF: 0.000212 AC: 236 AN: 1111864

Gnomad4 Remaining exome AF: 0.00340 AC: 205 AN: 60352

GnomAD4 genome AF: 0.0114 AC: 1742 AN: 152330 Hom.: 36 Cov.: 33 AF XY: 0.0108 AC XY: 807 AN XY: 74486

Gnomad4 AFR AF: 0.0382 AC: 0.0381878 AN: 0.0381878

Gnomad4 AMR AF: 0.00673 AC: 0.00672763 AN: 0.00672763

Gnomad4 ASJ AF: 0.00231 AC: 0.00230548 AN: 0.00230548

Gnomad4 EAS AF: 0.000193 AC: 0.000193349 AN: 0.000193349

Gnomad4 SAS AF: 0.000415 AC: 0.000414766 AN: 0.000414766

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000309 AC: 0.000308715 AN: 0.000308715

Gnomad4 OTH AF: 0.00898 AC: 0.00897921 AN: 0.00897921

Alfa AF: 0.00710 Hom.: 8

Bravo AF: 0.0133

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Nov 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 16, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	9.8
DANN	Benign	0.95
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs6832687; hg19: chr4-41259113;