X-48925888-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001136157.2(OTUD5):​c.1222G>T​(p.Asp408Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., 0 hem., cov: 22)
Failed GnomAD Quality Control

Consequence

OTUD5
NM_001136157.2 missense

Scores

8
8
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.08
Variant links:
Genes affected
OTUD5 (HGNC:25402): (OTU deubiquitinase 5) This gene encodes a member of the OTU (ovarian tumor) domain-containing cysteine protease superfamily. The OTU domain confers deubiquitinase activity and the encoded protein has been shown to suppress the type I interferon-dependent innate immune response by cleaving the polyubiquitin chain from an essential type I interferon adaptor protein. Cleavage results in disassociation of the adaptor protein from a downstream signaling complex and disruption of the type I interferon signaling cascade. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Oct 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.843

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
OTUD5NM_001136157.2 linkc.1222G>T p.Asp408Tyr missense_variant Exon 6 of 9 ENST00000376488.8 NP_001129629.1 Q96G74-5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
OTUD5ENST00000376488.8 linkc.1222G>T p.Asp408Tyr missense_variant Exon 6 of 9 1 NM_001136157.2 ENSP00000365671.3 Q96G74-5

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
0
AN:
111908
Hom.:
0
Cov.:
22
AF XY:
0.00
AC XY:
0
AN XY:
34078
FAILED QC
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
0.00
AC:
0
AN:
111908
Hom.:
0
Cov.:
22
AF XY:
0.00
AC XY:
0
AN XY:
34078
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
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

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Jul 25, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This missense change has been observed in individual(s) with clinical features of OTUD5-related conditions (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 413 of the OTUD5 protein (p.Asp413Tyr). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.94
BayesDel_addAF
Pathogenic
0.45
D
BayesDel_noAF
Pathogenic
0.40
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.69
.;.;D;.;T;.
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.97
D;D;D;.;D;D
M_CAP
Pathogenic
0.49
D
MetaRNN
Pathogenic
0.84
D;D;D;D;D;D
MetaSVM
Uncertain
0.60
D
MutationAssessor
Uncertain
2.2
.;.;M;.;.;.
PrimateAI
Uncertain
0.67
T
PROVEAN
Pathogenic
-6.8
D;D;D;D;.;D
REVEL
Uncertain
0.62
Sift
Pathogenic
0.0
D;D;D;D;.;D
Sift4G
Uncertain
0.0020
D;D;D;D;D;D
Polyphen
1.0
.;.;D;.;.;.
Vest4
0.61
MutPred
0.37
.;.;Loss of ubiquitination at K416 (P = 0.0246);.;.;.;
MVP
0.94
MPC
3.1
ClinPred
0.99
D
GERP RS
5.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.96
gMVP
0.99

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: chrX-48783164; API