X-48923877-G-C

Position:

chrX-48923877-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The ENST00000376488.8(OTUD5):c.1439C>G(p.Ala480Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000223 in 1,210,583 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000024 ( 0 hom. 7 hem. )

Consequence

OTUD5
ENST00000376488.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.20

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]

OTUD5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), OTUD5. . Gene score misZ 3.994 (greater than the threshold 3.09). GenCC has associacion of gene with multiple congenital anomalies-neurodevelopmental syndrome, X-linked, multiple congenital anomalies/dysmorphic syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.18868715).

BS2

High Hemizygotes in GnomAdExome4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTUD5	NM_001136157.2 linkuse as main transcript	c.1439C>G	p.Ala480Gly	missense_variant	7/9	ENST00000376488.8	NP_001129629.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTUD5	ENST00000376488.8 linkuse as main transcript	c.1439C>G	p.Ala480Gly	missense_variant	7/9	1	NM_001136157.2	ENSP00000365671	P4	Q96G74-5

Frequencies

GnomAD3 genomes

AF:

0.00000888

AC:

AN:

112643

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34793

show subpopulations

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000237

AC:

AN:

1097940

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

363310

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000297

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.00000888

AC:

AN:

112643

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34793

show subpopulations

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:

0.0000188

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 29, 2021

The c.1454C>G (p.A485G) alteration is located in exon 7 (coding exon 7) of the OTUD5 gene. This alteration results from a C to G substitution at nucleotide position 1454, causing the alanine (A) at amino acid position 485 to be replaced by a glycine (G). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is not well conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be tolerated by in silico analysis. 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

0.074

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.81

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.088

.;.;T;.;T;.

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.85

T;D;T;.;D;T

M_CAP

Benign

0.0089

MetaRNN

Benign

0.19

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.46

.;.;N;.;.;.

MutationTaster

Benign

0.91

D;D;D;D

PrimateAI

Uncertain

0.78

PROVEAN

Benign

0.45

N;N;N;N;.;N

REVEL

Benign

0.072

Sift

Benign

0.44

T;T;T;T;.;T

Sift4G

Benign

0.49

T;T;T;T;T;T

Polyphen

0.13

.;.;B;.;.;.

Vest4

0.098

MutPred

0.12

.;.;Loss of sheet (P = 0.0357);.;.;.;

MVP

0.23

MPC

1.5

ClinPred

0.86

GERP RS

4.2

Varity_R

0.19

gMVP

0.39

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