X-48925915-G-A

Position:

• chrX-48925915-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The ENST00000376488.8(OTUD5):​c.1195C>T​(p.Arg399Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 24)
• Consequence: OTUD5 ENST00000376488.8 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.37

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 Likely_pathogenic. Variant got 6 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.873
• PP5: Variant X-48925915-G-A is Pathogenic according to our data. Variant chrX-48925915-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 996326.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTUD5	NM_001136157.2	c.1195C>T	p.Arg399Trp	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.1195C>T	p.Arg399Trp	missense_variant	6/9	1	NM_001136157.2	ENSP00000365671	P4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.74	.;.;D;.;T;.
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.97	D;D;D;.;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Uncertain	2.3	.;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.9	D;D;D;D;.;D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D;D;D;D;.;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		1.0	.;.;D;.;.;.
Vest4		0.77
MutPred		0.54		.;.;Loss of disorder (P = 0.0139);.;.;.;
MVP		1.0
MPC		2.8
ClinPred		1.0	D
GERP RS		3.4
Varity_R		0.84
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs2063659512; hg19: chrX-48783191;