1-77697867-C-G

Variant names:

• chr1-77697867-C-G
• NM_201624.3:c.2574G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_201624.3(USP33):​c.2574G>C​(p.Arg858Ser) 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. 13/22 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: USP33 NM_201624.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.298
• Publications: 0 publications found

Genes affected

USP33 (HGNC:20059): (ubiquitin specific peptidase 33) This gene encodes a deubiquinating enzyme important in a variety of processes, including Slit-dependent cell migration and beta-2 adrenergic receptor signaling. The protein is negatively regulated through ubiquitination by von Hippel-Lindau tumor protein (VHL). Alternative splicing results in multiple transcript variants and protein isoforms. [provided by RefSeq, Jun 2012]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1586946).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_201624.3. 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
	USP33	NM_201624.3	MANE Select	c.2574G>C	p.Arg858Ser	missense	Exon 23 of 24	NP_963918.1	Q8TEY7-2
	USP33	NM_015017.5		c.2667G>C	p.Arg889Ser	missense	Exon 24 of 25	NP_055832.3
	USP33	NM_001377430.1		c.2643G>C	p.Arg881Ser	missense	Exon 24 of 25	NP_001364359.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP33	ENST00000370794.7	TSL:1 MANE Select	c.2574G>C	p.Arg858Ser	missense	Exon 23 of 24	ENSP00000359830.3	Q8TEY7-2
	USP33	ENST00000370793.5	TSL:1	c.2667G>C	p.Arg889Ser	missense	Exon 24 of 25	ENSP00000359829.1	Q8TEY7-1
	USP33	ENST00000357428.5	TSL:5	c.2667G>C	p.Arg889Ser	missense	Exon 23 of 24	ENSP00000350009.1	Q8TEY7-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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	0.85
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.30
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.078
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.030	D
Polyphen		0.066	B
Vest4		0.34
MutPred		0.40		Loss of catalytic residue at M887 (P = 0.0286)
MVP		0.18
MPC		0.86
ClinPred		0.91	D
GERP RS		2.4
Varity_R		0.32
gMVP		0.53
Mutation Taster		=63/37	polymorphism

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: chr1-78163552;