X-48923188-G-T

Position:

• chrX-48923188-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The ENST00000376488.8(OTUD5):​c.1687C>A​(p.Pro563Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Synonymous variant affecting the same amino acid position (i.e. P563P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: OTUD5 ENST00000376488.8 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 4.57

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 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2751082).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTUD5	NM_001136157.2	c.1687C>A	p.Pro563Thr	missense_variant	9/9	ENST00000376488.8	NP_001129629.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTUD5	ENST00000376488.8	c.1687C>A	p.Pro563Thr	missense_variant	9/9	1	NM_001136157.2	ENSP00000365671	P4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Ependymoma Uncertain:1

Uncertain significance, no assertion criteria provided

research

McDonnell Genome Institute, Washington University in St. Louis

Dec 29, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	.;.;T;.;T;.
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.87	D;D;D;.;D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.28	T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.97	.;.;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.1	N;N;N;N;.;N
REVEL	Benign	0.11
Sift	Uncertain	0.0030	D;D;D;D;.;D
Sift4G	Uncertain	0.030	D;D;D;D;D;D
Polyphen		0.14	.;.;B;.;.;.
Vest4		0.27
MutPred		0.26		.;.;Gain of phosphorylation at P568 (P = 0.0081);.;.;.;
MVP		0.45
MPC		2.6
ClinPred		0.80	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.62
gMVP		0.64

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

Other links and lift over

dbSNP: rs1295653938; hg19: chrX-48780465;