Genetic Variant NM_032582.4:c.4573G>A (chr17-60180613-C-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_032582.4(USP32):c.4573G>A(p.Gly1525Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,474 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

USP32
NM_032582.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.87

Publications

0 publications found

Variant links:

Genes affected

USP32 (HGNC:19143): (ubiquitin specific peptidase 32) Enables thiol-dependent deubiquitinase. Predicted to be involved in protein deubiquitination. Located in Golgi apparatus and cytosol. [provided by Alliance of Genome Resources, Apr 2022]

USP32 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP32	NM_032582.4 link	c.4573G>A	p.Gly1525Ser	missense_variant	Exon 33 of 34	ENST00000300896.9	NP_115971.2	Q8NFA0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
USP32	ENST00000300896.9 link	c.4573G>A	p.Gly1525Ser	missense_variant	Exon 33 of 34	1	NM_032582.4	ENSP00000300896.3	Q8NFA0-1
USP32	ENST00000592339.5 link	c.3583G>A	p.Gly1195Ser	missense_variant	Exon 25 of 26	1		ENSP00000467885.1	K7EQL6
USP32	ENST00000593071.1 link	c.348+711G>A		intron_variant	Intron 1 of 1	5		ENSP00000466740.1	K7EN13

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461474

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727060

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111726

Other (OTH)

AF:

0.00

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 28, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.4573G>A (p.G1525S) alteration is located in exon 33 (coding exon 33) of the USP32 gene. This alteration results from a G to A substitution at nucleotide position 4573, causing the glycine (G) at amino acid position 1525 to be replaced by a serine (S). 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

0.99

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

T;.

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Uncertain

0.69

MutationAssessor

Uncertain

2.7

M;.

PhyloP100

7.9

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-5.2

D;.

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

D;.

Sift4G

Uncertain

0.0090

D;D

Polyphen

1.0

D;.

Vest4

0.89

MutPred

0.95

Gain of phosphorylation at T1529 (P = 0.1905);.;

MVP

0.82

MPC

1.5

ClinPred

1.0

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.90

gMVP

0.86

Mutation Taster

=20/80

disease causing

(source)

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

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NM_032582.4:c.4573G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over