chr1-77714760-T-C

Variant names:

• chr1-77714760-T-C
• rs144899790
• NM_201624.3:c.2069A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_201624.3(USP33):​c.2069A>G​(p.Lys690Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000618 in 1,612,108 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (2 hom.)
• Consequence: USP33 NM_201624.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.98
• Publications: 4 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03999728).
• BS2: High Homozygotes in GnomAdExome4 at 2 gene

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.2069A>G	p.Lys690Arg	missense	Exon 19 of 24	NP_963918.1	Q8TEY7-2
	USP33	NM_015017.5		c.2162A>G	p.Lys721Arg	missense	Exon 20 of 25	NP_055832.3
	USP33	NM_001377430.1		c.2138A>G	p.Lys713Arg	missense	Exon 20 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.2069A>G	p.Lys690Arg	missense	Exon 19 of 24	ENSP00000359830.3	Q8TEY7-2
	USP33	ENST00000370793.5	TSL:1	c.2162A>G	p.Lys721Arg	missense	Exon 20 of 25	ENSP00000359829.1	Q8TEY7-1
	USP33	ENST00000370792.7	TSL:1	c.2138A>G	p.Lys713Arg	missense	Exon 20 of 22	ENSP00000359828.3	Q8TEY7-3

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000191 AC: 48 AN: 250846 AF XY: 0.000184

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000396

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000657 AC: 959 AN: 1459896 Hom.: 2 Cov.: 31 AF XY: 0.000638 AC XY: 463 AN XY: 726234

African (AFR) AF: 0.000180 AC: 6 AN: 33406

American (AMR) AF: 0.0000224 AC: 1 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.00 AC: 0 AN: 86074

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4494

European-Non Finnish (NFE) AF: 0.000825 AC: 917 AN: 1111884

Other (OTH) AF: 0.000581 AC: 35 AN: 60232

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.000323 AC XY: 24 AN XY: 74358

African (AFR) AF: 0.000193 AC: 8 AN: 41468

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68038

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000460 Hom.: 0

Bravo AF: 0.000227

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000140 AC: 17

EpiCase AF: 0.000382

EpiControl AF: 0.000296

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	0.071
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	18
DANN	Benign	0.065
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.28	N
PhyloP100		2.0
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.11
Sift	Benign	1.0	T
Sift4G	Benign	0.78	T
Polyphen		0.0	B
Vest4		0.13
MVP		0.27
MPC		0.51
ClinPred		0.012	T
GERP RS		4.0
Varity_R		0.041
gMVP		0.28
Mutation Taster		=99/1	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

dbSNP: rs144899790; hg19: chr1-78180445;