chr15-63574069-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_006537.4(USP3):​c.932C>T​(p.Thr311Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000188 in 1,592,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

USP3
NM_006537.4 missense

Scores

6
8
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91
Variant links:
Genes affected
USP3 (HGNC:12626): (ubiquitin specific peptidase 3) Enables histone binding activity and thiol-dependent deubiquitinase. Involved in several processes, including DNA repair; histone deubiquitination; and regulation of protein stability. Located in several cellular components, including Flemming body; cytoplasmic ribonucleoprotein granule; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]
USP3-AS1 (HGNC:44140): (USP3 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.787

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
USP3NM_006537.4 linkc.932C>T p.Thr311Met missense_variant 10/15 ENST00000380324.8 NP_006528.2 Q9Y6I4-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
USP3ENST00000380324.8 linkc.932C>T p.Thr311Met missense_variant 10/151 NM_006537.4 ENSP00000369681.3 Q9Y6I4-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152094
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000966
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000121
AC:
3
AN:
247228
Hom.:
0
AF XY:
0.00000748
AC XY:
1
AN XY:
133758
show subpopulations
Gnomad AFR exome
AF:
0.0000620
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000559
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000889
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000180
AC:
26
AN:
1440670
Hom.:
0
Cov.:
30
AF XY:
0.0000237
AC XY:
17
AN XY:
715884
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000255
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000227
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152094
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74296
show subpopulations
Gnomad4 AFR
AF:
0.0000966
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:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000116
Hom.:
0
Bravo
AF:
0.0000227
ExAC
AF:
0.0000165
AC:
2

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 GeneticsMay 02, 2024The c.932C>T (p.T311M) alteration is located in exon 10 (coding exon 10) of the USP3 gene. This alteration results from a C to T substitution at nucleotide position 932, causing the threonine (T) at amino acid position 311 to be replaced by a methionine (M). 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
0.40
BayesDel_addAF
Uncertain
0.059
T
BayesDel_noAF
Uncertain
0.030
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.14
.;T;T;T;.
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;D;D;D;D
M_CAP
Benign
0.047
D
MetaRNN
Pathogenic
0.79
D;D;D;D;D
MetaSVM
Benign
-0.88
T
MutationAssessor
Benign
1.9
.;L;.;.;.
PrimateAI
Uncertain
0.74
T
PROVEAN
Uncertain
-3.1
D;D;D;D;D
REVEL
Uncertain
0.40
Sift
Uncertain
0.0010
D;D;D;D;D
Sift4G
Uncertain
0.0040
D;D;D;D;D
Polyphen
1.0
.;D;D;.;.
Vest4
0.73
MVP
0.27
MPC
1.4
ClinPred
0.84
D
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.75

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: rs747289460; hg19: chr15-63866268; COSMIC: COSV51426385; API