12-6856134-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001098536.2(USP5):ā€‹c.422A>Cā€‹(p.Asp141Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000242 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: š‘“ 0.000079 ( 0 hom., cov: 32)
Exomes š‘“: 0.000018 ( 0 hom. )

Consequence

USP5
NM_001098536.2 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.83
Variant links:
Genes affected
USP5 (HGNC:12628): (ubiquitin specific peptidase 5) Ubiquitin (see MIM 191339)-dependent proteolysis is a complex pathway of protein metabolism implicated in such diverse cellular functions as maintenance of chromatin structure, receptor function, and degradation of abnormal proteins. A late step of the process involves disassembly of the polyubiquitin chains on degraded proteins into ubiquitin monomers. USP5 disassembles branched polyubiquitin chains by a sequential exo mechanism, starting at the proximal end of the chain (Wilkinson et al., 1995 [PubMed 7578059]).[supplied by OMIM, Mar 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.14881304).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
USP5NM_001098536.2 linkuse as main transcriptc.422A>C p.Asp141Ala missense_variant 4/20 ENST00000229268.13 NP_001092006.1 P45974-1A0A140VJZ1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
USP5ENST00000229268.13 linkuse as main transcriptc.422A>C p.Asp141Ala missense_variant 4/201 NM_001098536.2 ENSP00000229268.8 P45974-1
USP5ENST00000389231.9 linkuse as main transcriptc.422A>C p.Asp141Ala missense_variant 4/201 ENSP00000373883.5 P45974-2
USP5ENST00000542087.1 linkuse as main transcriptc.357+65A>C intron_variant 3 ENSP00000444668.1 F5H571

Frequencies

GnomAD3 genomes
AF:
0.0000789
AC:
12
AN:
152120
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
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:
0.000103
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251466
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135910
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:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000185
AC:
27
AN:
1461886
Hom.:
0
Cov.:
34
AF XY:
0.0000179
AC XY:
13
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
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:
0.0000216
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000789
AC:
12
AN:
152120
Hom.:
0
Cov.:
32
AF XY:
0.0000673
AC XY:
5
AN XY:
74312
show subpopulations
Gnomad4 AFR
AF:
0.000121
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:
0.000103
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000772
Hom.:
0
Bravo
AF:
0.0000567
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

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 submitterclinical testingAmbry GeneticsDec 04, 2024The c.422A>C (p.D141A) alteration is located in exon 4 (coding exon 4) of the USP5 gene. This alteration results from a A to C substitution at nucleotide position 422, causing the aspartic acid (D) at amino acid position 141 to be replaced by an alanine (A). 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
0.13
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.51
CADD
Benign
22
DANN
Benign
0.89
DEOGEN2
Benign
0.12
T;.
Eigen
Benign
-0.32
Eigen_PC
Benign
-0.068
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Benign
0.68
T;T
M_CAP
Benign
0.0066
T
MetaRNN
Benign
0.15
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.97
L;L
PrimateAI
Uncertain
0.50
T
PROVEAN
Benign
-0.050
N;N
REVEL
Benign
0.11
Sift
Benign
0.70
T;T
Sift4G
Benign
0.67
T;T
Polyphen
0.0
B;B
Vest4
0.50
MutPred
0.46
Gain of catalytic residue at L136 (P = 2e-04);Gain of catalytic residue at L136 (P = 2e-04);
MVP
0.16
MPC
0.87
ClinPred
0.31
T
GERP RS
4.8
Varity_R
0.20
gMVP
0.60

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs782408714; hg19: chr12-6965298; API