Variant chr1-193028145-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001199261.3(UCHL5):c.569C>G(p.Ala190Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000756 in 1,587,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000056 ( 0 hom. )

Consequence

UCHL5
NM_001199261.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.07

Variant links:

Genes affected

UCHL5 (HGNC:19678): (ubiquitin C-terminal hydrolase L5) Enables endopeptidase inhibitor activity; proteasome binding activity; and thiol-dependent deubiquitinase. Involved in negative regulation of proteasomal ubiquitin-dependent protein catabolic process; positive regulation of smoothened signaling pathway; and protein deubiquitination. Located in cytosol; nucleolus; and nucleoplasm. Colocalizes with Ino80 complex. [provided by Alliance of Genome Resources, Apr 2022]

UCHL5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2595496).

BS2

High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UCHL5	NM_001199261.3 linkuse as main transcript	c.569C>G	p.Ala190Gly	missense_variant	7/11	ENST00000367454.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UCHL5	ENST00000367454.6 linkuse as main transcript	c.569C>G	p.Ala190Gly	missense_variant	7/11	1	NM_001199261.3	A1	Q9Y5K5-3

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

151998

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000858

AC:

AN:

233032

Hom.:

AF XY:

0.0000158

AC XY:

AN XY:

126380

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000185

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000557

AC:

AN:

1435052

Hom.:

Cov.:

AF XY:

0.00000561

AC XY:

AN XY:

713204

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000726

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

151998

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74234

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2023

The c.569C>G (p.A190G) alteration is located in exon 7 (coding exon 7) of the UCHL5 gene. This alteration results from a C to G substitution at nucleotide position 569, causing the alanine (A) at amino acid position 190 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.29

T;.;T;T;.;.;.

Eigen

Benign

0.082

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.91

D;D;D;D;D;D;D

M_CAP

Benign

0.012

MetaRNN

Benign

0.26

T;T;T;T;T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.2

L;L;.;.;L;L;.

MutationTaster

Benign

0.67

N;N;N;N;N;N;N

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.9

N;N;N;N;N;N;N

REVEL

Benign

0.053

Sift

Benign

0.30

T;T;T;T;T;T;T

Sift4G

Benign

0.23

T;T;T;T;T;T;T

Polyphen

0.0010

B;B;.;.;B;B;.

Vest4

0.29

MutPred

0.40

Loss of catalytic residue at A190 (P = 0.1046);Loss of catalytic residue at A190 (P = 0.1046);.;Loss of catalytic residue at A190 (P = 0.1046);Loss of catalytic residue at A190 (P = 0.1046);Loss of catalytic residue at A190 (P = 0.1046);.;

MVP

0.20

MPC

0.66

ClinPred

0.16

GERP RS

3.2

Varity_R

0.22

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over