X-48925989-T-C

Position:

• chrX-48925989-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The ENST00000376488.8(OTUD5):​c.1121A>G​(p.Gln374Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: OTUD5 ENST00000376488.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.88

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTUD5	NM_001136157.2	c.1121A>G	p.Gln374Arg	missense_variant	6/9	ENST00000376488.8	NP_001129629.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTUD5	ENST00000376488.8	c.1121A>G	p.Gln374Arg	missense_variant	6/9	1	NM_001136157.2	ENSP00000365671	P4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Multiple congenital anomalies-neurodevelopmental syndrome, X-linked Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

MVZ Medizinische Genetik Mainz

Jun 07, 2022

ACMG Criteria: PP2, PM2, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	.;.;D;.;T;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D;D;.;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.70	D;D;D;D;D;D
MetaSVM	Uncertain	0.091	D
MutationAssessor	Benign	1.7	.;.;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.8	D;D;D;D;.;D
REVEL	Uncertain	0.49
Sift	Benign	0.033	D;D;D;D;.;D
Sift4G	Benign	0.15	T;T;T;T;T;T
Polyphen		0.60	.;.;P;.;.;.
Vest4		0.69
MutPred		0.42		.;.;Gain of loop (P = 0.0312);.;.;.;
MVP		0.84
MPC		2.1
ClinPred		0.93	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.67
gMVP		0.95

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-48783265;