15-63532660-C-A

Position:

• chr15-63532660-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006537.4(USP3):​c.105C>A​(p.Asn35Lys) 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. 12/20 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: 2.71

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 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=0.25439954).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP3	NM_006537.4	c.105C>A	p.Asn35Lys	missense_variant	2/15	ENST00000380324.8	NP_006528.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP3	ENST00000380324.8	c.105C>A	p.Asn35Lys	missense_variant	2/15	1	NM_006537.4	ENSP00000369681.3

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

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 2023

The c.105C>A (p.N35K) alteration is located in exon 2 (coding exon 2) of the USP3 gene. This alteration results from a C to A substitution at nucleotide position 105, causing the asparagine (N) at amino acid position 35 to be replaced by a lysine (K). 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	0.81
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.014	.;T;T;T;T;T;T;T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.25	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.73	N;.;.;N;.;.;.;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.38	N;N;N;N;N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.30	T;T;T;T;T;T;T;T
Sift4G	Benign	0.68	T;T;T;T;T;T;T;T
Polyphen		0.54	.;.;.;P;.;.;P;.
Vest4		0.59
MutPred		0.60		Gain of methylation at N35 (P = 0.0086);.;Gain of methylation at N35 (P = 0.0086);Gain of methylation at N35 (P = 0.0086);.;.;.;.;
MVP		0.21
MPC		1.5
ClinPred		0.59	D
GERP RS		6.2
Varity_R		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr15-63824859;