15-63588768-G-A

Variant names:

• chr15-63588768-G-A
• rs201397735
• NM_006537.4:c.1282G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006537.4(USP3):​c.1282G>A​(p.Val428Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000545 in 1,614,176 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 (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: USP3 NM_006537.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.91
• Publications: 2 publications found

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41967055).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006537.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP3	NM_006537.4	MANE Select	c.1282G>A	p.Val428Ile	missense	Exon 13 of 15	NP_006528.2	Q9Y6I4-1
	USP3	NM_001256702.2		c.1150G>A	p.Val384Ile	missense	Exon 12 of 14	NP_001243631.1	Q9Y6I4-2
	USP3-AS1	NR_034080.1		n.664C>T		non_coding_transcript_exon	Exon 3 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP3	ENST00000380324.8	TSL:1 MANE Select	c.1282G>A	p.Val428Ile	missense	Exon 13 of 15	ENSP00000369681.3	Q9Y6I4-1
	USP3	ENST00000558285.5	TSL:1	c.1231G>A	p.Val411Ile	missense	Exon 12 of 14	ENSP00000453619.1	H0YMI4
	USP3	ENST00000538686.6	TSL:1	n.*1135G>A		non_coding_transcript_exon	Exon 12 of 14	ENSP00000445793.2

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000438 AC: 11 AN: 251394 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000527 AC: 77 AN: 1461848 Hom.: 0 Cov.: 31 AF XY: 0.0000509 AC XY: 37 AN XY: 727226

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000576 AC: 64 AN: 1111970

Other (OTH) AF: 0.0000331 AC: 2 AN: 60394

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74496

African (AFR) AF: 0.0000962 AC: 4 AN: 41564

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.0000718

ExAC AF: 0.0000247 AC: 3

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.043	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.86	L
PhyloP100		9.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.24
Sift	Benign	0.21	T
Sift4G	Benign	0.34	T
Polyphen		0.99	D
Vest4		0.66
MVP		0.25
MPC		1.2
ClinPred		0.37	T
GERP RS		4.5
Varity_R		0.12
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs201397735; hg19: chr15-63880967; COSMIC: COSV51426732; COSMIC: COSV51426732;