Genetic Variant USP42:p.Arg303Ser (chr7-6144115-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_032172.3(USP42):c.909G>T(p.Arg303Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,427,576 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

USP42
NM_032172.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.649

Publications

0 publications found

Variant links:

Genes affected

USP42 (HGNC:20068): (ubiquitin specific peptidase 42) Enables thiol-dependent deubiquitinase. Involved in protein deubiquitination. Predicted to be located in nucleoplasm. Predicted to be active in cytosol and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

USP42 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 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
USP42	NM_032172.3 link	c.909G>T	p.Arg303Ser	missense_variant	Exon 9 of 18	ENST00000306177.10	NP_115548.1	Q9H9J4-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP42	ENST00000306177.10 link	c.909G>T	p.Arg303Ser	missense_variant	Exon 9 of 18	5	NM_032172.3	ENSP00000301962.5		Q9H9J4-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.00e-7

AC:

AN:

1427576

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

709340

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31078

American (AMR)

AF:

0.00

AC:

AN:

36008

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25466

East Asian (EAS)

AF:

0.00

AC:

AN:

37004

South Asian (SAS)

AF:

0.00

AC:

AN:

78768

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53114

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

9.08e-7

AC:

AN:

1101378

Other (OTH)

AF:

0.00

AC:

AN:

59066

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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

Jan 24, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.909G>T (p.R303S) alteration is located in exon 9 (coding exon 8) of the USP42 gene. This alteration results from a G to T substitution at nucleotide position 909, causing the arginine (R) at amino acid position 303 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

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.011

.;T;T

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.77

T;T;T

M_CAP

Benign

0.035

MetaRNN

Uncertain

0.57

D;D;D

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.99

L;.;.

PhyloP100

-0.65

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-5.2

D;D;D

REVEL

Uncertain

0.30

Sift

Benign

0.033

D;T;D

Sift4G

Pathogenic

0.0

D;T;D

Polyphen

0.54

P;.;.

Vest4

0.89

MutPred

0.63

Loss of MoRF binding (P = 0.0224);.;.;

MVP

0.82

MPC

2.3

ClinPred

0.98

GERP RS

-2.0

gMVP

0.66

Mutation Taster

=42/58

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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7-6144115-G-T

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