1-77722154-T-G

Variant names:

• chr1-77722154-T-G
• NM_201624.3:c.1432A>C

Variant summary

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

The NM_201624.3(USP33):​c.1432A>C​(p.Ile478Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 7.67

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

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	c.1432A>C	p.Ile478Leu	missense_variant	Exon 13 of 24	ENST00000370794.7	NP_963918.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP33	ENST00000370794.7	c.1432A>C	p.Ile478Leu	missense_variant	Exon 13 of 24	1	NM_201624.3	ENSP00000359830.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1525A>C (p.I509L) alteration is located in exon 14 (coding exon 13) of the USP33 gene. This alteration results from a A to C substitution at nucleotide position 1525, causing the isoleucine (I) at amino acid position 509 to be replaced by a leucine (L). 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	0.73
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.095	.;T;T;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D;D;.;D
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.52	D;D;D;D
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.6	.;L;L;L
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.7	N;N;N;N
REVEL	Benign	0.29
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.012	D;D;D;D
Polyphen		0.99	D;D;D;D
Vest4		0.63
MutPred		0.41		.;Gain of disorder (P = 0.0727);Gain of disorder (P = 0.0727);Gain of disorder (P = 0.0727);
MVP		0.46
MPC		1.6
ClinPred		0.93	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.52
gMVP		0.58

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-78187839;