NM_006537.4:c.794T>C

Variant names:

• chr15-63570465-T-C
• NM_006537.4:c.794T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006537.4(USP3):​c.794T>C​(p.Met265Thr) 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.98
• Publications: 0 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.906

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.794T>C	p.Met265Thr	missense	Exon 9 of 15	NP_006528.2	Q9Y6I4-1
	USP3	NM_001256702.2		c.662T>C	p.Met221Thr	missense	Exon 8 of 14	NP_001243631.1	Q9Y6I4-2
	USP3	NR_046341.2		n.1094T>C		non_coding_transcript_exon	Exon 10 of 16

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP3	ENST00000380324.8	TSL:1 MANE Select	c.794T>C	p.Met265Thr	missense	Exon 9 of 15	ENSP00000369681.3	Q9Y6I4-1
	USP3	ENST00000558285.5	TSL:1	c.743T>C	p.Met248Thr	missense	Exon 8 of 14	ENSP00000453619.1	H0YMI4
	USP3	ENST00000538686.6	TSL:1	n.*647T>C		non_coding_transcript_exon	Exon 8 of 14	ENSP00000445793.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		8.0
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.60	P
Vest4		0.85
MutPred		0.83		Loss of stability (P = 0.1147)
MVP		0.49
MPC		0.82
ClinPred		0.98	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
Mutation Taster		=34/66	disease causing

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

Other links and lift over

hg19: chr15-63862664;