4-143185555-G-C

Variant summary

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

The NM_032557.6(USP38):​c.105G>C​(p.Glu35Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,614,016 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: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

USP38
NM_032557.6 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0310
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]

Genome browser will be placed here

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=0.028301805).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
USP38NM_032557.6 linkc.105G>C p.Glu35Asp missense_variant Exon 1 of 10 ENST00000307017.9 NP_115946.2 Q8NB14-1
USP38NM_001410848.1 linkc.105G>C p.Glu35Asp missense_variant Exon 1 of 9 NP_001397777.1
USP38NM_001290325.1 linkc.105G>C p.Glu35Asp missense_variant Exon 1 of 9 NP_001277254.1 Q8NB14-2
USP38NM_001290326.1 linkc.-1377G>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
USP38ENST00000307017.9 linkc.105G>C p.Glu35Asp missense_variant Exon 1 of 10 1 NM_032557.6 ENSP00000303434.4 Q8NB14-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152214
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000916
AC:
23
AN:
251162
Hom.:
0
AF XY:
0.0000663
AC XY:
9
AN XY:
135768
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000665
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
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:
0.0000226
AC:
33
AN:
1461802
Hom.:
0
Cov.:
31
AF XY:
0.0000206
AC XY:
15
AN XY:
727190
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000738
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152214
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74364
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000264
ExAC
AF:
0.0000988
AC:
12

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Oct 25, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.105G>C (p.E35D) 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 105, causing the glutamic acid (E) at amino acid position 35 to be replaced by an aspartic acid (D). 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
0.12
BayesDel_addAF
Benign
-0.42
T
BayesDel_noAF
Benign
-0.48
CADD
Benign
18
DANN
Uncertain
0.99
DEOGEN2
Benign
0.036
.;T
Eigen
Benign
-0.50
Eigen_PC
Benign
-0.39
FATHMM_MKL
Benign
0.26
N
LIST_S2
Benign
0.63
T;T
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.028
T;T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
1.4
L;L
PrimateAI
Benign
0.27
T
PROVEAN
Benign
-0.83
N;N
REVEL
Benign
0.028
Sift
Benign
0.19
T;T
Sift4G
Benign
0.49
T;T
Polyphen
0.060
.;B
Vest4
0.097
MutPred
0.18
Loss of helix (P = 0.3949);Loss of helix (P = 0.3949);
MVP
0.59
MPC
0.78
ClinPred
0.041
T
GERP RS
3.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.18
gMVP
0.17

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.

Other links and lift over

dbSNP: rs766262970; hg19: chr4-144106708; API