chrX-48923180-C-G

Variant names:

• chrX-48923180-C-G
• NM_001136157.2:c.1695G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001136157.2(OTUD5):​c.1695G>C​(p.Lys565Asn) 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 benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: OTUD5 NM_001136157.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.88
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• multiple congenital anomalies-neurodevelopmental syndrome, X-linked

  Inheritance: XL Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen
• multiple congenital anomalies/dysmorphic syndrome

  Inheritance: XL Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 6 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 3.994 (above the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to multiple congenital anomalies-neurodevelopmental syndrome, X-linked, multiple congenital anomalies/dysmorphic syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.122829586).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001136157.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTUD5	NM_001136157.2	MANE Select	c.1695G>C	p.Lys565Asn	missense	Exon 9 of 9	NP_001129629.1	Q96G74-5
	OTUD5	NM_017602.4		c.1710G>C	p.Lys570Asn	missense	Exon 9 of 9	NP_060072.1	Q96G74-1
	OTUD5	NM_001136158.2		c.1695G>C	p.Lys565Asn	missense	Exon 9 of 10	NP_001129630.1	Q96G74-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTUD5	ENST00000376488.8	TSL:1 MANE Select	c.1695G>C	p.Lys565Asn	missense	Exon 9 of 9	ENSP00000365671.3	Q96G74-5
	OTUD5	ENST00000156084.8	TSL:1	c.1710G>C	p.Lys570Asn	missense	Exon 9 of 9	ENSP00000156084.4	Q96G74-1
	OTUD5	ENST00000396743.7	TSL:1	c.1695G>C	p.Lys565Asn	missense	Exon 9 of 10	ENSP00000379969.3	Q96G74-5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		2.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.035
Sift	Benign	0.077	T
Sift4G	Benign	0.38	T
Polyphen		0.12	B
Vest4		0.25
MutPred		0.12		Loss of ubiquitination at K570 (P = 0.003)
MVP		0.26
MPC		1.8
ClinPred		0.51	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.17
Mutation Taster		=78/22	polymorphism

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

Other links and lift over

hg19: chrX-48780457;