chr1-193029302-T-C

Position:

• chr1-193029302-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001199261.3(UCHL5):​c.442A>G​(p.Met148Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: UCHL5 NM_001199261.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.61

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UCHL5	NM_001199261.3	c.442A>G	p.Met148Val	missense_variant	6/11	ENST00000367454.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UCHL5	ENST00000367454.6	c.442A>G	p.Met148Val	missense_variant	6/11	1	NM_001199261.3	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 02, 2022

The c.442A>G (p.M148V) alteration is located in exon 6 (coding exon 6) of the UCHL5 gene. This alteration results from a A to G substitution at nucleotide position 442, causing the methionine (M) at amino acid position 148 to be replaced by a valine (V). 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	Uncertain	0.35
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	27
DANN	Benign	0.72
DEOGEN2	Benign	0.22	T;.;T;T;.;.;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.41	T;T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.27	N;N;.;.;N;N;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.5	N;N;N;N;N;N;N
REVEL	Benign	0.25
Sift	Benign	0.22	T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T
Polyphen		0.0040	B;B;.;.;B;B;.
Vest4		0.68
MutPred		0.41		Loss of phosphorylation at T153 (P = 0.0814);Loss of phosphorylation at T153 (P = 0.0814);.;Loss of phosphorylation at T153 (P = 0.0814);Loss of phosphorylation at T153 (P = 0.0814);Loss of phosphorylation at T153 (P = 0.0814);.;
MVP		0.57
MPC		0.65
ClinPred		0.65	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.40
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.36		Position offset: 3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553247236; hg19: chr1-192998432;