Genetic Variant USP38:p.Arg98Ser (chr4-143185744-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_032557.6(USP38):c.294G>C(p.Arg98Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

USP38
NM_032557.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.457

Variant links:

Genes affected

USP38 (HGNC:20067): (ubiquitin specific peptidase 38) Enables thiol-dependent deubiquitinase. Involved in protein deubiquitination. Predicted to be active in cytosol and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

USP38 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.057673365).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP38	NM_032557.6 link	c.294G>C	p.Arg98Ser	missense_variant	Exon 1 of 10	ENST00000307017.9	NP_115946.2	Q8NB14-1
USP38	NM_001410848.1 link	c.294G>C	p.Arg98Ser	missense_variant	Exon 1 of 9		NP_001397777.1
USP38	NM_001290325.1 link	c.294G>C	p.Arg98Ser	missense_variant	Exon 1 of 9		NP_001277254.1	Q8NB14-2
USP38	NM_001290326.1 link	c.-1188G>C		5_prime_UTR_variant	Exon 1 of 11		NP_001277255.1	Q8NB14B3KSB9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP38	ENST00000307017.9 link	c.294G>C	p.Arg98Ser	missense_variant	Exon 1 of 10	1	NM_032557.6	ENSP00000303434.4		Q8NB14-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251450

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

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

Feb 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.294G>C (p.R98S) alteration is located in exon 1 (coding exon 1) of the USP38 gene. This alteration results from a G to C substitution at nucleotide position 294, causing the arginine (R) at amino acid position 98 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

Benign

0.26

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.022

.;T

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.058

LIST_S2

Benign

0.77

T;T

M_CAP

Benign

0.0051

MetaRNN

Benign

0.058

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.4

L;L

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.54

N;N

REVEL

Benign

0.098

Sift

Benign

0.23

T;T

Sift4G

Benign

0.48

T;T

Polyphen

0.025

.;B

Vest4

0.20

MutPred

0.36

Gain of disorder (P = 0.0345);Gain of disorder (P = 0.0345);

MVP

0.17

MPC

0.91

ClinPred

0.047

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.20

gMVP

0.33

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over