X-48923701-G-A

Position:

• chrX-48923701-G-A

Variant summary

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

The NM_001136157.2(OTUD5):​c.1511C>T​(p.Pro504Leu) 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 NM_001136157.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 5.45

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.1511C>T	p.Pro504Leu	missense_variant	8/9	ENST00000376488.8	NP_001129629.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTUD5	ENST00000376488.8	c.1511C>T	p.Pro504Leu	missense_variant	8/9	1	NM_001136157.2	ENSP00000365671	P4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 20, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 36879111) -

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

Uncertain significance, no assertion criteria provided

research

Laboratory of Medical Genetics, University of Torino

Oct 09, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	0.0090	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	.;.;T;.;T;.
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.93	D;D;D;.;D;D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.49	T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.7	.;.;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-4.0	D;D;D;D;.;D
REVEL	Benign	0.16
Sift	Uncertain	0.0010	D;D;D;D;.;D
Sift4G	Uncertain	0.024	D;D;D;D;D;D
Polyphen		0.61	.;.;P;.;.;.
Vest4		0.16
MutPred		0.40		.;.;Loss of disorder (P = 0.0268);.;.;.;
MVP		0.36
MPC		1.5
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.46
gMVP		0.50

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-48780978;