chr15-63553726-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_006537.4(USP3):​c.296A>T​(p.Asp99Val) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

USP3
NM_006537.4 missense

Scores

11
6
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.32
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)

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.865

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
USP3NM_006537.4 linkc.296A>T p.Asp99Val missense_variant 4/15 ENST00000380324.8 NP_006528.2 Q9Y6I4-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
USP3ENST00000380324.8 linkc.296A>T p.Asp99Val missense_variant 4/151 NM_006537.4 ENSP00000369681.3 Q9Y6I4-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

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 GeneticsJun 11, 2024The c.296A>T (p.D99V) alteration is located in exon 4 (coding exon 4) of the USP3 gene. This alteration results from a A to T substitution at nucleotide position 296, causing the aspartic acid (D) at amino acid position 99 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
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.33
D
BayesDel_noAF
Pathogenic
0.23
CADD
Pathogenic
34
DANN
Uncertain
0.99
DEOGEN2
Benign
0.064
.;T;T;T;T;T;T;.
Eigen
Pathogenic
0.98
Eigen_PC
Pathogenic
0.94
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.99
D;D;D;D;D;D;D;D
M_CAP
Uncertain
0.15
D
MetaRNN
Pathogenic
0.87
D;D;D;D;D;D;D;D
MetaSVM
Uncertain
-0.24
T
MutationAssessor
Pathogenic
3.7
.;.;.;H;.;.;.;.
PrimateAI
Pathogenic
0.85
D
PROVEAN
Pathogenic
-6.2
D;D;D;D;D;D;D;D
REVEL
Uncertain
0.61
Sift
Uncertain
0.0020
D;D;D;D;D;D;D;D
Sift4G
Uncertain
0.0020
D;D;D;D;D;D;D;D
Polyphen
0.96
.;.;.;D;.;D;.;.
Vest4
0.81
MutPred
0.73
.;.;.;Loss of catalytic residue at D99 (P = 0.0651);.;.;.;.;
MVP
0.59
MPC
1.6
ClinPred
1.0
D
GERP RS
6.1
Varity_R
0.82

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-63845925; API