1-161160662-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_001014443.3(USP21):​c.22C>T​(p.Arg8Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R8H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

USP21
NM_001014443.3 missense

Scores

4
6
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.58
Variant links:
Genes affected
USP21 (HGNC:12620): (ubiquitin specific peptidase 21) This gene encodes a member of the C19 peptidase family, also known as family 2 of ubiquitin carboxy-terminal hydrolases. The encoded protein cleaves ubiquitin from ubiquitinated proteins for recycling in intracellular protein degradation. The encoded protein is also able to release NEDD8, a ubiquitin-like protein, from NEDD8-conjugated proteins. This gene has been referred to as USP16 and USP23 but is now known as USP21. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2016]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.2744391).
BS2
High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
USP21NM_001014443.3 linkc.22C>T p.Arg8Cys missense_variant Exon 3 of 14 ENST00000368002.8 NP_001014443.1 Q9UK80-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
USP21ENST00000368002.8 linkc.22C>T p.Arg8Cys missense_variant Exon 3 of 14 1 NM_001014443.3 ENSP00000356981.3 Q9UK80-1
USP21ENST00000289865.12 linkc.22C>T p.Arg8Cys missense_variant Exon 2 of 13 1 ENSP00000289865.8 Q9UK80-1
USP21ENST00000368001.1 linkc.22C>T p.Arg8Cys missense_variant Exon 2 of 13 1 ENSP00000356980.1 Q9UK80-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
250980
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135688
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:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000411
AC:
6
AN:
1461552
Hom.:
0
Cov.:
31
AF XY:
0.00000688
AC XY:
5
AN XY:
727054
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:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000312
Hom.:
0
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Sep 29, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.22C>T (p.R8C) alteration is located in exon 3 (coding exon 1) of the USP21 gene. This alteration results from a C to T substitution at nucleotide position 22, causing the arginine (R) at amino acid position 8 to be replaced by a cysteine (C). 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
0.47
BayesDel_addAF
Uncertain
0.094
D
BayesDel_noAF
Benign
-0.10
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.013
.;T;T;T;.
Eigen
Uncertain
0.45
Eigen_PC
Uncertain
0.51
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Uncertain
0.92
D;D;.;D;D
M_CAP
Benign
0.0079
T
MetaRNN
Benign
0.27
T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.20
.;N;N;.;N
PrimateAI
Pathogenic
0.80
T
PROVEAN
Benign
-0.64
.;N;N;.;N
REVEL
Benign
0.20
Sift
Pathogenic
0.0
.;D;D;.;D
Sift4G
Pathogenic
0.0
D;D;D;D;D
Polyphen
1.0
.;D;D;.;.
Vest4
0.69, 0.71, 0.71
MutPred
0.23
Loss of MoRF binding (P = 0.006);Loss of MoRF binding (P = 0.006);Loss of MoRF binding (P = 0.006);Loss of MoRF binding (P = 0.006);Loss of MoRF binding (P = 0.006);
MVP
0.66
MPC
0.21
ClinPred
0.56
D
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.23
gMVP
0.38

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs780961535; hg19: chr1-161130452; COSMIC: COSV57091564; COSMIC: COSV57091564; API