15-63537078-C-G

Variant names:

• chr15-63537078-C-G
• NM_006537.4:c.206C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006537.4(USP3):​c.206C>G​(p.Thr69Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.255

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.066649884).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP3	NM_006537.4	c.206C>G	p.Thr69Ser	missense_variant	Exon 3 of 15	ENST00000380324.8	NP_006528.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP3	ENST00000380324.8	c.206C>G	p.Thr69Ser	missense_variant	Exon 3 of 15	1	NM_006537.4	ENSP00000369681.3

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

Oct 10, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.206C>G (p.T69S) alteration is located in exon 3 (coding exon 3) of the USP3 gene. This alteration results from a C to G substitution at nucleotide position 206, causing the threonine (T) at amino acid position 69 to be replaced by a serine (S). 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	0.060
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	13
DANN	Benign	0.92
DEOGEN2	Benign	0.0062	T;T;T;T;T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.48
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.56	T;T;T;T;T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.067	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.47	.;N;.;.;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.51	N;N;N;N;N
REVEL	Benign	0.092
Sift	Benign	0.53	T;T;T;T;T
Sift4G	Benign	0.30	T;T;T;T;T
Polyphen		0.0	.;B;.;B;.
Vest4		0.23, 0.17, 0.19
MutPred		0.47		.;Gain of ubiquitination at K72 (P = 0.0571);.;.;.;
MVP		0.36
MPC		0.42
ClinPred		0.057	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.052

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-63829277;