chr17-60180613-C-T

Position:

• chr17-60180613-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.87

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 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/exons	MANE	Protein	UniProt
USP32	NM_032582.4	c.4573G>A	p.Gly1525Ser	missense_variant	33/34	ENST00000300896.9	NP_115971.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP32	ENST00000300896.9	c.4573G>A	p.Gly1525Ser	missense_variant	33/34	1	NM_032582.4	ENSP00000300896.3
USP32	ENST00000592339.5	c.3583G>A	p.Gly1195Ser	missense_variant	25/26	1		ENSP00000467885.1
USP32	ENST00000593071.1	c.348+711G>A		intron_variant		5		ENSP00000466740.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461474 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727060

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 28, 2023

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	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Uncertain	2.7	M;.
PrimateAI	Uncertain	0.77	T
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	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.86

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-58257974;