Genetic Variant NM_201624.3:c.2073G>C (chr1-77714756-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_201624.3(USP33):c.2073G>C(p.Glu691Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000203 in 1,612,148 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

USP33
NM_201624.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.669

Variant links:

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]

USP33 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP33	NM_201624.3 link	c.2073G>C	p.Glu691Asp	missense_variant	Exon 19 of 24	ENST00000370794.7	NP_963918.1	Q8TEY7-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP33	ENST00000370794.7 link	c.2073G>C	p.Glu691Asp	missense_variant	Exon 19 of 24	1	NM_201624.3	ENSP00000359830.3		Q8TEY7-2

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000718

AC:

AN:

250838

Hom.:

AF XY:

0.0000664

AC XY:

AN XY:

135588

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000212

AC:

309

AN:

1459952

Hom.:

Cov.:

AF XY:

0.000204

AC XY:

148

AN XY:

726288

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000225

Gnomad4 NFE exome

AF:

0.000261

Gnomad4 OTH exome

AF:

0.0000996

GnomAD4 genome

AF:

0.000125

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000158

Hom.:

Bravo

AF:

0.000102

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2166G>C (p.E722D) alteration is located in exon 20 (coding exon 19) of the USP33 gene. This alteration results from a G to C substitution at nucleotide position 2166, causing the glutamic acid (E) at amino acid position 722 to be replaced by an aspartic acid (D). 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

Uncertain

0.46

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.040

.;T;T;.

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.21

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.94

D;D;.;D

M_CAP

Benign

0.048

MetaRNN

Uncertain

0.45

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

.;L;L;.

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.2

N;N;N;N

REVEL

Benign

0.15

Sift

Benign

0.045

D;T;T;T

Sift4G

Benign

0.58

T;T;T;T

Polyphen

0.98

D;D;D;D

Vest4

0.57

MutPred

0.23

.;Gain of MoRF binding (P = 0.1141);Gain of MoRF binding (P = 0.1141);.;

MVP

0.47

MPC

1.5

ClinPred

0.24

GERP RS

2.3

Varity_R

0.12

gMVP

0.65

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over